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Jeong JH, Kim YG, Han KD, Roh SY, Lee HS, Choi YY, Shim J, Kim YH, Choi JI. Proteinuria Is Associated With an Increased Risk of Sudden Cardiac Arrest in the Young Population. J Am Heart Assoc 2025; 14:e036077. [PMID: 40079300 DOI: 10.1161/jaha.124.036077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 12/20/2024] [Indexed: 03/15/2025]
Abstract
BACKGROUND Proteinuria is a risk factor for cardiovascular events, but its prognostic value for sudden cardiac arrest (SCA) in young individuals remains unproven. We aimed to evaluate whether proteinuria in young people is associated with an increased risk of SCA. METHODS AND RESULTS Individuals aged between 20 and 39 years who underwent health screening between 2009 and 2012 in South Korea were included (n=6 891 400). Urine protein was measured using the spot urine dipstick method. Main outcome was SCA identified by International Classification of Diseases, Tenth Revision (ICD-10). Participants included in the analysis were followed-up till December 2020, and Cox proportional hazards model was used to demonstrate the risk of SCA. The mean age was 30.9±5.0 years, and 3 775 535 (59.5%) were men. The mean follow-up duration was 9.4±1.2 years. During follow-up, SCA occurred in 5352 individuals (0.08%). Participants with proteinuria had a higher incidence of SCA (n=182, incidence rate 0.19, during 962 956 person-year follow-up) than those without proteinuria (n=5170, incidence rate 0.09, during 58 465 181 person-year follow-up). Adjustment of confounders resulted higher risk of SCA in participants with proteinuria (adjusted hazard ratio 1.71 [95% CI=1.47-1.99], P<0.001). Participants with proteinuria +3-4 showed a significant increase in the risk of SCA (2.94 [1.96-4.40], P<0.001). The influence of proteinuria on SCA was stronger in advanced chronic kidney disease (stage 3 and stage 4-5). CONCLUSIONS Proteinuria was significantly associated with an increased risk of SCA in young people. Individuals with pre-existing chronic kidney disease showed a stronger association between proteinuria and the risk of SCA.
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Affiliation(s)
- Joo Hee Jeong
- Division of Cardiology, Department of Internal Medicine Korea University College of Medicine and Korea University Anam Hospital Seoul Republic of Korea
| | - Yun Gi Kim
- Division of Cardiology, Department of Internal Medicine Korea University College of Medicine and Korea University Anam Hospital Seoul Republic of Korea
| | - Kyung-Do Han
- Department of Statistics and Actuarial Science Soongsil University Seoul Republic of Korea
| | - Seung-Young Roh
- Division of Cardiology, Department of Internal Medicine Korea University College of Medicine, and Korea University Guro Hospital Seoul Republic of Korea
| | - Hyoung Seok Lee
- Division of Cardiology, Department of Internal Medicine Korea University College of Medicine and Korea University Anam Hospital Seoul Republic of Korea
| | - Yun Young Choi
- Division of Cardiology, Department of Internal Medicine Korea University College of Medicine and Korea University Anam Hospital Seoul Republic of Korea
| | - Jaemin Shim
- Division of Cardiology, Department of Internal Medicine Korea University College of Medicine and Korea University Anam Hospital Seoul Republic of Korea
| | - Young-Hoon Kim
- Division of Cardiology, Department of Internal Medicine Korea University College of Medicine and Korea University Anam Hospital Seoul Republic of Korea
| | - Jong-Il Choi
- Division of Cardiology, Department of Internal Medicine Korea University College of Medicine and Korea University Anam Hospital Seoul Republic of Korea
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Taha HSE, Momtaz M, Elamragy AA, Younis O, Fahim MAS. Heart failure with reduced ejection fraction and chronic kidney disease: a focus on therapies and interventions. Heart Fail Rev 2025; 30:159-175. [PMID: 39419850 DOI: 10.1007/s10741-024-10453-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/09/2024] [Indexed: 10/19/2024]
Abstract
In heart failure with reduced ejection fraction (HFrEF), the presence of concomitant chronic kidney disease (CKD) predicts poorer cardiovascular outcomes, more aggravated heart failure (HF) status, and higher mortality. Physicians might be reluctant to initiate life-saving anti-HF medications out of fear of worsening renal function and a higher incidence of adverse events. Moreover, international guidelines do not give clear recommendations on managing this subgroup of patients as well as advanced CKD was always an exclusion criterion in most major HF trials. Nevertheless, in this review, we will highlight several recent clinical trials and post-hoc analyses of major trials that showed the safety and efficacy of the different therapies in HFrEF patients with CKD, besides several small-scale cohorts that tested guideline-directed medical therapies in End Stage Kidney Disease (ESKD). Regarding interventions in this subgroup of patients, we will provide up-to-date data on implantable cardioverter defibrillators, cardiac resynchronization therapy, and coronary revascularization, in addition to mitral valve transcatheter edge-to-edge repair and implantable pulmonary artery pressure sensors.
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Affiliation(s)
| | - Mohamed Momtaz
- Nephrology & Internal Medicine, Internal Medicine Department, Kasr Al-Ainy Faculty of Medicine, Cairo University, Giza, Egypt
| | - Ahmed Adel Elamragy
- Cardiology Department, Kasr Al-Ainy Faculty of Medicine, Cairo University, Giza, Egypt
| | - Omar Younis
- Cardiology Department, National Heart Institute, 5 Ibn Al Nafees Square, Al Kit Kat, Giza, 12651, Egypt.
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Chaudhry K, Karalliedde J. Chronic kidney disease in type 2 diabetes: The size of the problem, addressing residual renal risk and what we have learned from the CREDENCE trial. Diabetes Obes Metab 2024; 26 Suppl 5:25-34. [PMID: 39044385 DOI: 10.1111/dom.15765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/07/2024] [Accepted: 06/19/2024] [Indexed: 07/25/2024]
Abstract
Chronic kidney disease (CKD) associated with type 2 diabetes (T2DM) is a global challenge; progression to end-stage kidney disease (ESKD) and increased risk of cardiovascular disease (CVD) associated with advancing nephropathy are a significant source of morbidity, mortality, and healthcare expenditure. Until recently, renin-angiotensin system (RAS) blockade was the mainstay of pharmacotherapy in diabetic kidney disease (DKD), representing a therapeutic paradigm shift towards interventions that delay disease progression independently of antihypertensive effects. However, a significant residual risk of DKD progression persisted in patients established on RAS blockade, highlighting the need for additional treatment options. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally licensed as glucose-lowering agents in people with T2DM, serendipitously demonstrated beneficial renal and cardiovascular outcomes in clinical trials designed primarily to evaluate their cardiovascular safety. The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was the first to study the effect of SGLT2 inhibition on a primary composite renal endpoint of ESKD, doubling of serum creatinine, or renal or cardiovascular death in 4401 people with T2DM and CKD established on RAS blockade. The trial was stopped early due to efficacy, demonstrating a 30% relative risk reduction in the primary endpoint in the canagliflozin group (hazard ratio 0.70, 95% confidence interval 0.59-0.82; p = 0.00001). Through discussion of the primary analysis from CREDENCE, and selected post hoc analyses, we review the significant benefits highlighted by this landmark study, its role in shaping clinical guidelines, and in re-establishing interest in interventions that reduce the residual risk of progression of DKD, alongside its interrelation with cardiovascular morbidity and heart failure. We also provide a brief narrative summary of key renal outcome trials since CREDENCE, which indicate emerging avenues for pharmacotherapy beyond SGLT2 inhibition.
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Affiliation(s)
- Khuram Chaudhry
- Department of Diabetes and Endocrinology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Janaka Karalliedde
- Department of Diabetes and Endocrinology, Guy's and St Thomas' NHS Foundation Trust, London, UK
- School of Cardiovascular, Metabolic Medicine and Sciences, King's College London, London, UK
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Kugathasan L, Sridhar VS, Lytvyn Y, Lovblom LE, Perkins BA, Advani A, Cherney DZI. Effect of hyperglycemia and empagliflozin on markers of cardiorenal injury and inflammation in patients with type 1 diabetes. Diabetes Res Clin Pract 2024; 213:111764. [PMID: 38960044 DOI: 10.1016/j.diabres.2024.111764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/19/2024] [Accepted: 07/01/2024] [Indexed: 07/05/2024]
Abstract
AIMS To investigate the effect of hyperglycemia and empagliflozin on cardiorenal injury and inflammation in patients with uncomplicated type 1 diabetes (T1D). METHODS Serum cardiac (sST2, Gal-3, cTnT), kidney injury (KIM-1, NGAL), inflammatory (sTNFR1, sTNFR2), and hemodynamic (NT-proBNP, EPO) markers were assessed post-hoc in two separate T1D cohorts. The glycemic clamp trial (NCT02344602) evaluated 49 adults with T1D and 27 controls under euglycemic and acute hyperglycemic conditions. The crossover BETWEEN trial (NCT02632747) investigated empagliflozin 25 mg plus ramipril for 4 weeks compared to placebo-ramipril for 4 weeks in 30 adults with T1D. RESULTS In the glycemic clamp study, hyperglycemia acutely increased levels of NT-proBNP (p = 0.0003) and sTNFR2 (p = 0.003). BETWEEN participants treated with empagliflozin exhibited a paradoxical subacute rise in NT-proBNP (p = 0.0147) compared to placebo, independent of hematocrit. Individuals with higher baseline levels of sST2 and sTNFR1 had greater empagliflozin-associated reductions in systolic blood pressure and greater activation of renin-angiotensin-aldosterone system (RAAS) mediators, whereas those with higher baseline levels of KIM-1 and sTNFR1 had greater glomerular filtration rate (GFR) dip. CONCLUSION The protective mechanisms of SGLT2 inhibition on blood pressure, RAAS activation, and renal hemodynamics are apparent in the subset of people with uncomplicated T1D with adverse cardiorenal and inflammatory markers.
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Affiliation(s)
- Luxcia Kugathasan
- Department of Medicine, Division of Nephrology, University Health Network, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada; Temerty Faculty of Medicine, University of Toronto, 2109 Medical Sciences Building, 1 King's College Cir, Toronto, Ontario M5S 1A8, Canada; Cardiovascular Sciences Collaborative Specialization, University of Toronto, 263 McCaul St, P.O. Box 3C, 4th Floor, Rm 413, Toronto, Ontario M5T 1W7, Canada.
| | - Vikas S Sridhar
- Department of Medicine, Division of Nephrology, University Health Network, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada; Temerty Faculty of Medicine, University of Toronto, 2109 Medical Sciences Building, 1 King's College Cir, Toronto, Ontario M5S 1A8, Canada.
| | - Yuliya Lytvyn
- Department of Medicine, Division of Nephrology, University Health Network, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada; Temerty Faculty of Medicine, University of Toronto, 2109 Medical Sciences Building, 1 King's College Cir, Toronto, Ontario M5S 1A8, Canada.
| | - Leif Erik Lovblom
- Biostatistics Department, University Health Network, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada.
| | - Bruce A Perkins
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Ave Toronto, Ontario M5G 1X5, Canada; Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, 6 Queen's Park Crescent West, Third Floor, Toronto, Ontario M5S 3H2, Canada.
| | - Andrew Advani
- Temerty Faculty of Medicine, University of Toronto, 2109 Medical Sciences Building, 1 King's College Cir, Toronto, Ontario M5S 1A8, Canada; Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St Michael's Hospital, 209 Victoria St, Toronto, Ontario M5B 1T8, Canada.
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada; Temerty Faculty of Medicine, University of Toronto, 2109 Medical Sciences Building, 1 King's College Cir, Toronto, Ontario M5S 1A8, Canada; Cardiovascular Sciences Collaborative Specialization, University of Toronto, 263 McCaul St, P.O. Box 3C, 4th Floor, Rm 413, Toronto, Ontario M5T 1W7, Canada.
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Dai M, Hua S, Yang J, Geng D, Li W, Hu S, Chen H, Liao X. Incidence and risk factors of asymptomatic bacteriuria in patients with type 2 diabetes mellitus: a meta-analysis. Endocrine 2023; 82:263-281. [PMID: 37599328 PMCID: PMC10543815 DOI: 10.1007/s12020-023-03469-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 06/28/2023] [Indexed: 08/22/2023]
Abstract
BACKGROUND The prevalence of type 2 diabetes mellitus (T2DM) is increasing each year and has become one of the most prominent health concerns worldwide. Patients with T2DM are prone to infectious diseases, and urinary tract infections are also widespread. Despite a comprehensive understanding of urinary tract infection (UTI), there is a lack of research regarding primary prevention strategies for asymptomatic bacteriuria (ASB). OBJECTIVE To clarify the incidence and risk factors of asymptomatic urinary tract infection in patients with T2DM by meta-analysis to provide evidence for preventing UTI. Help patients, their families, and caregivers to identify the risk factors of patients in time and intervene to reduce the incidence of ASB in patients with T2DM. Fill in the gaps in existing research. STUDY DESIGN Meta-analyses were conducted in line with PRISMA guidelines. METHODS Eleven databases were systematically searched for articles about ASB in T2DM, and the retrieval time was selected from the establishment of the database to February 5, 2023. Literature screening, quality evaluation, and meta-analysis were independently performed by two researchers according to the inclusion and exclusion criteria, and a meta-analysis was performed using Stata 17.0. RESULTS Fourteen articles were included, including cohort and case-control studies. A meta-analysis of 4044 patients with T2DM was included. The incidence of ASB in patients with T2DM was 23.7%(95% CI (0.183, 0.291); P < 0.001). After controlling for confounding variables, the following risk factors were associated with ASB in patients with T2DM: age (WMD = 3.18, 95% CI (1.91, 4.45), I2 = 75.5%, P < 0.001), female sex (OR = 1.07, 95% CI(1.02, 1.12), I2 = 79.3%, P = 0.002), duration of type 2 diabetes (WMD = 2.54, 95% CI (1.53, 5.43), I2 = 80.7%, P < 0.001), HbA1c (WMD = 0.63, 95% CI (0.43, 0.84), I2 = 62.6,%. P < 0.001), hypertension (OR = 1.59, 95% CI (1.24, 2.04), I2 = 0%, <0.001), hyperlipidemia (OR = 1.66, 95% CI (1.27, 2.18), I2 = 0%, P < 0.001), Neuropathy (OR = 1.81, 95% CI (1.38, 2.37), I2 = 0%, P < 0.001), proteinuria (OR = 3.00, 95% CI (1.82, 4.95), I2 = 62.7%, P < 0.001). CONCLUSION The overall prevalence of ASB in T2DM is 23.7%. Age, female sex, course of T2DM, HbA1C, hypertension, hyperlipidemia, neuropathy, and proteinuria were identified as related risk factors for ASB in T2DM. These findings can provide a robust theoretical basis for preventing and managing ASB in T2DM.
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Affiliation(s)
- Mengqiao Dai
- Shanghai University of Traditional Chinese Medicine, School of Nursing, Shanghai, 201203, China
| | - Shan Hua
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiechao Yang
- Shanghai University of Traditional Chinese Medicine, School of Nursing, Shanghai, 201203, China
| | - Dandan Geng
- Shanghai University of Traditional Chinese Medicine, School of Nursing, Shanghai, 201203, China
| | - Weina Li
- Shanghai University of Traditional Chinese Medicine, School of Nursing, Shanghai, 201203, China
| | - Shuqin Hu
- Shanghai University of Traditional Chinese Medicine, School of Nursing, Shanghai, 201203, China
| | - Hu Chen
- Shanghai University of Traditional Chinese Medicine, School of Nursing, Shanghai, 201203, China
| | - Xiaoqin Liao
- Shanghai University of Traditional Chinese Medicine, School of Nursing, Shanghai, 201203, China.
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Wang X, Ren L, Huang Y, Feng Z, Zhang G, Dai H. The Role of Tubulointerstitial Markers in Differential Diagnosis and Prognosis in Patients with Type 2 Diabetes and Biopsy Proven Diabetic Kidney Disease. Clin Chim Acta 2023:117448. [PMID: 37331550 DOI: 10.1016/j.cca.2023.117448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 05/15/2023] [Accepted: 06/13/2023] [Indexed: 06/20/2023]
Abstract
OBJECTIVE To evaluate the potential application of tubularinterstitial biomarkers in the differential diagnosis of diabetic kidney disease (DKD) from non-diabetic kidney disease (NDKD), as well as investigate key clinical and pathological parameters to help improve the stratification of patients according to end-stage renal disease risk. METHODS 132 type 2 diabetic patients with chronic kidney disease were enrolled. Patients were categorized into 2 groups according to the renal biopsy results: DKD (n=61) and NDKD (n=71).The independent factors of the occurrence of DKD and the diagnostic implications of tubular biomarkers were explored by logistic regression and receiver-operating characteristic curve analysis. Furthermore, predictors were analyzed by least absolute shrinkage and selection operator regression, and constructed a new model for predicting the unfavorable renal outcomes through Cox proportional hazard regression analysis. RESULTS Serum neutrophil gelatinase-associated lipocalin (sNGAL) (OR= 1.007; 95%CI = [1.003, 1.012], p = 0.001) was identified as an independent risk factor for the occurrence of DKD in diabetic patients with CKD. Tubular biomarkers including sNGAL, N-acetyl-β-D-glucosaminidase and β2 microglobulin (β2-MG) could complement albuminuria for DKD detection (AUC = 0.926, specificity = 90.14%, sensitivity = 80.33%).Moreover, among of the 47 variables, 4 predictors such as sNGAL, interstitial fibrosis and tubular atrophy (IFTA)score, β2-MG and estimated glomerular filtration rate were selected to construct a new model for predicting the unfavorable renal outcomes through regression analysis. sNGAL (HR = 1.004; 95%CI = [1.001, 1.007], p = 0.013), IFTA score of 2 (HR = 4.283; 95%CI = [1.086, 16.881], p = 0.038), and IFTA score of 3 (HR = 6.855; 95%CI = [1.766, 26.610], p = 0.005) were considered to be independent risk factors for unfavorable renal outcomes. CONCLUSIONS Tubulointerstitial injury in DKD is independently associated with renal function decline and routinely detected tubular biomarkers are able to enhance the level of non-invasive diagnosis of DKD beyond traditional factors.
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Affiliation(s)
- Xijian Wang
- Department of Nephrology, Affiliated Hospital of Nantong University, Nantong Jiangsu, 226001, PR China
| | - Liang Ren
- Department of Nephrology, Affiliated Hospital of Nantong University, Nantong Jiangsu, 226001, PR China
| | - Ying Huang
- Department of Nephrology, Affiliated Hospital of Nantong University, Nantong Jiangsu, 226001, PR China
| | - Zhengang Feng
- Department of Nephrology, Affiliated Hospital of Nantong University, Nantong Jiangsu, 226001, PR China
| | - Guangdi Zhang
- Department of Nephrology, Affiliated Hospital of Nantong University, Nantong Jiangsu, 226001, PR China
| | - Houyong Dai
- Department of Nephrology, Affiliated Hospital of Nantong University, Nantong Jiangsu, 226001, PR China.
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Schoettler ML, Carreras E, Cho B, Dandoy CE, Ho VT, Jodele S, Moissev I, Sanchez-Ortega I, Srivastava A, Atsuta Y, Carpenter P, Koreth J, Kroger N, Ljungman P, Page K, Popat U, Shaw BE, Sureda A, Soiffer R, Vasu S. Harmonizing Definitions for Diagnostic Criteria and Prognostic Assessment of Transplantation-Associated Thrombotic Microangiopathy: A Report on Behalf of the European Society for Blood and Marrow Transplantation, American Society for Transplantation and Cellular Therapy, Asia-Pacific Blood and Marrow Transplantation Group, and Center for International Blood and Marrow Transplant Research. Transplant Cell Ther 2023; 29:151-163. [PMID: 36442770 PMCID: PMC10119629 DOI: 10.1016/j.jtct.2022.11.015] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 11/18/2022] [Indexed: 11/27/2022]
Abstract
Transplantation-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic cell transplantation (HCT) associated with significant morbidity and mortality. However, TA-TMA is a clinical diagnosis, and multiple criteria have been proposed without universal application. Although some patients have a self-resolving disease, others progress to multiorgan failure and/or death. Poor prognostic features also are not uniformly accepted. The lack of harmonization of diagnostic and prognostic markers has precluded multi-institutional studies to better understand incidence and outcomes. Even current interventional trials use different criteria, making it challenging to interpret the data. To address this urgent need, the American Society for Transplantation and Cellular Therapy, Center for International Bone Marrow Transplant Research, Asia-Pacific Blood and Marrow Transplantation, and European Society for Blood and Marrow Transplantation nominated representatives for an expert panel tasked with reaching consensus on diagnostic and prognostic criteria. The panel reviewed literature, generated consensus statements regarding diagnostic and prognostic features of TA-TMA using the Delphi method, and identified future directions of investigation. Consensus was reached on 4 key concepts: (1) TA-TMA can be diagnosed using clinical and laboratory criteria or tissue biopsy of kidney or gastrointestinal tissue; however, biopsy is not required; (2) consensus diagnostic criteria are proposed using the modified Jodele criteria with additional definitions of anemia and thrombocytopenia. TA-TMA is diagnosed when ≥4 of the following 7 features occur twice within 14 days: anemia, defined as failure to achieve transfusion independence despite neutrophil engraftment; hemoglobin decline by ≥1 g/dL or new-onset transfusion dependence; thrombocytopenia, defined as failure to achieve platelet engraftment, higher-than-expected transfusion needs, refractory to platelet transfusions, or ≥50% reduction in baseline platelet count after full platelet engraftment; lactate dehydrogenase (LDH) exceeding the upper limit of normal (ULN); schistocytes; hypertension; soluble C5b-9 (sC5b-9) exceeding the ULN; and proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio [rUPCR]); (3) patients with any of the following features are at increased risk of nonrelapse mortality and should be stratified as high-risk TA-TMA: elevated sC5b-9, LDH ≥2 times the ULN, rUPCR ≥1 mg/mg, multiorgan dysfunction, concurrent grade II-IV acute graft-versus-host disease (GVHD), or infection (bacterial or viral); and (4) all allogeneic and pediatric autologous HCT recipients with neuroblastoma should be screened weekly for TA-TMA during the first 100 days post-HCT. Patients diagnosed with TA-TMA should be risk-stratified, and those with high-risk disease should be offered participation in a clinical trial for TA-TMA-directed therapy if available. We propose that these criteria and risk stratification features be used in data registries, prospective studies, and clinical practice across international settings. This harmonization will facilitate the investigation of TA-TMA across populations diverse in race, ethnicity, age, disease indications, and transplantation characteristics. As these criteria are widely used, we expect continued refinement as necessary. Efforts to identify more specific diagnostic and prognostic biomarkers are a top priority of the field. Finally, an investigation of the impact of TA-TMA-directed treatment, particularly in the setting of concurrent highly morbid complications, such as steroid-refractory GVHD and infection, is critically needed.
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Affiliation(s)
- M L Schoettler
- Department Blood and Marrow Transplantation, Children's Healthcare of Atlanta, Aflac Cancer and Blood Disorders Center, Atlanta, Georgia
| | - E Carreras
- Spanish Bone Marrow Donor Registry, Josep Carreras Foundation and Leukemia Research Institute, Barcelona, Catalunya, Spain
| | - B Cho
- Department of Internal Medicine, Catholic Blood and Marrow Transplantation Center, Seoul, Korea
| | - C E Dandoy
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - V T Ho
- Department of Medical Oncology, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA
| | - S Jodele
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - I Moissev
- RM Gorbacheva Research Institute, Pavlov University, Saint-Petersburg, Russian Federation
| | | | - A Srivastava
- Department of Haematology, Christian Medical College, Vellore, India
| | - Y Atsuta
- Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan
| | - P Carpenter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - J Koreth
- Department of Medical Oncology, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA
| | - N Kroger
- Division of Hematology, Ohio State University, Columbus, Ohio
| | - P Ljungman
- Department of Cellular Therapy and Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - K Page
- Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - U Popat
- Department of Stem Cell Transplantation & Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - B E Shaw
- Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Division of Pediatric Hematology/Oncology/Blood and Marrow Transplant, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - A Sureda
- Clinical Hematology Department, Institut Català d'Oncologia-Hospitalet, Barcelona, Spain
| | - R Soiffer
- Department of Medical Oncology, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA
| | - S Vasu
- Division of Hematology, Ohio State University, Columbus, Ohio.
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Gnudi L. Renal disease in patients with type 2 diabetes: Magnitude of the problem, risk factors and preventive strategies. Presse Med 2023; 52:104159. [PMID: 36565753 DOI: 10.1016/j.lpm.2022.104159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Luigi Gnudi
- School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.
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Mangelis A, Fountoulakis N, Corcillo A, Collins J, Vas P, Hussain S, Hopkins D, Gnudi L, Thomas S, Ayis S, Karalliedde J. African Caribbean Ethnicity Is an Independent Predictor of Significant Decline in Kidney Function in People With Type 1 Diabetes. Diabetes Care 2022; 45:2095-2102. [PMID: 36044663 DOI: 10.2337/dc22-0815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 05/22/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The aim of the study was to identify the demographic and clinical features in an urban cohort of people with type 1 diabetes who developed a ≥50% decline in estimated glomerular filtration rate (eGFR). RESEARCH DESIGN AND METHODS We evaluated 5,261 people with type 1 diabetes (51% female, 13.4% African Caribbean) with baseline eGFR >45 mL/min/1.73 m2 between 2004 and 2018. The primary end point was an eGFR decline of ≥50% from baseline with a final eGFR <30 mL/min/1.73 m2. eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation. RESULTS Of the cohort, 263 (5%) reached the primary end point. These individuals were more likely to be of African Caribbean ethnicity, be older, have a longer duration of diabetes, have higher systolic blood pressure and HbA1c, have more prevalent retinopathy, and have higher albuminuria (all P < 0.05). In multivariable Cox regression models, African Caribbean ethnicity emerged as a significant risk factor for the primary end point (hazard ratio 1.57, 95% CI 1.19, 2.08) compared with other ethnicities and independent of established risk factors (P < 0.01). The incidence rate for the primary end point in African Caribbean people was double that in non-African Caribbean people (16 vs. 7.7 per 1000 patient-years, P < 0.001). A similar significant independent impact of African Caribbean ethnicity for secondary end points (≥40% and ≥30% fall in eGFR) was observed. CONCLUSIONS We report a novel observation that African Caribbean ethnicity increased the risk of kidney function loss in people with type 1 diabetes, an effect that was independent of traditional risk factors. Further studies are needed to examine the associated pathophysiology that may explain this observation.
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Affiliation(s)
- Anastasios Mangelis
- School of Population Health and Environmental Sciences, King's College London, London, U.K
| | - Nikolaos Fountoulakis
- King's Health Partners and School of Cardiovascular Medicine and Sciences, King's College London, London, U.K
| | - Antonella Corcillo
- King's Health Partners and School of Cardiovascular Medicine and Sciences, King's College London, London, U.K
| | - Julian Collins
- King's Health Partners and School of Cardiovascular Medicine and Sciences, King's College London, London, U.K
| | - Prashant Vas
- King's Health Partners and School of Cardiovascular Medicine and Sciences, King's College London, London, U.K
| | - Sufyan Hussain
- King's Health Partners and School of Cardiovascular Medicine and Sciences, King's College London, London, U.K
| | - David Hopkins
- King's Health Partners and School of Cardiovascular Medicine and Sciences, King's College London, London, U.K
| | - Luigi Gnudi
- King's Health Partners and School of Cardiovascular Medicine and Sciences, King's College London, London, U.K
| | - Stephen Thomas
- King's Health Partners and School of Cardiovascular Medicine and Sciences, King's College London, London, U.K
| | - Salma Ayis
- School of Population Health and Environmental Sciences, King's College London, London, U.K
| | - Janaka Karalliedde
- King's Health Partners and School of Cardiovascular Medicine and Sciences, King's College London, London, U.K
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10
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Correia GDS, Takis PG, Sands CJ, Kowalka AM, Tan T, Turtle L, Ho A, Semple MG, Openshaw PJM, Baillie JK, Takáts Z, Lewis MR. 1H NMR Signals from Urine Excreted Protein Are a Source of Bias in Probabilistic Quotient Normalization. Anal Chem 2022; 94:6919-6923. [PMID: 35503092 PMCID: PMC9118196 DOI: 10.1021/acs.analchem.2c00466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Normalization to account for variation in urinary dilution is crucial for interpretation of urine metabolic profiles. Probabilistic quotient normalization (PQN) is used routinely in metabolomics but is sensitive to systematic variation shared across a large proportion of the spectral profile (>50%). Where 1H nuclear magnetic resonance (NMR) spectroscopy is employed, the presence of urinary protein can elevate the spectral baseline and substantially impact the resulting profile. Using 1H NMR profile measurements of spot urine samples collected from hospitalized COVID-19 patients in the ISARIC 4C study, we determined that PQN coefficients are significantly correlated with observed protein levels (r2 = 0.423, p < 2.2 × 10-16). This correlation was significantly reduced (r2 = 0.163, p < 2.2 × 10-16) when using a computational method for suppression of macromolecular signals known as small molecule enhancement spectroscopy (SMolESY) for proteinic baseline removal prior to PQN. These results highlight proteinuria as a common yet overlooked source of bias in 1H NMR metabolic profiling studies which can be effectively mitigated using SMolESY or other macromolecular signal suppression methods before estimation of normalization coefficients.
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Affiliation(s)
- Gonçalo D. S. Correia
- Section
of Bioanalytical Chemistry, Division of Systems Medicine, Department
of Metabolism, Digestion and Reproduction, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
- National
Phenome Centre, Imperial College London, Hammersmith Campus, IRDB Building, London W12 0NN, United Kingdom
- G. D. S. Correia.
| | - Panteleimon G. Takis
- Section
of Bioanalytical Chemistry, Division of Systems Medicine, Department
of Metabolism, Digestion and Reproduction, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
- National
Phenome Centre, Imperial College London, Hammersmith Campus, IRDB Building, London W12 0NN, United Kingdom
- P. G. Takis.
| | - Caroline J. Sands
- Section
of Bioanalytical Chemistry, Division of Systems Medicine, Department
of Metabolism, Digestion and Reproduction, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
- National
Phenome Centre, Imperial College London, Hammersmith Campus, IRDB Building, London W12 0NN, United Kingdom
| | - Anna M. Kowalka
- Division
of Diabetes, Endocrinology and Metabolism, Department of Metabolism,
Digestion and Reproduction, Imperial College
London, Du Cane Road, London W12 0NN, United Kingdom
- Clinical
Biochemistry, Blood Sciences, North West London Pathology, Charing Cross Hospital, London W6 8RF, United Kingdom
| | - Tricia Tan
- Division
of Diabetes, Endocrinology and Metabolism, Department of Metabolism,
Digestion and Reproduction, Imperial College
London, Du Cane Road, London W12 0NN, United Kingdom
- Clinical
Biochemistry, Blood Sciences, North West London Pathology, Charing Cross Hospital, London W6 8RF, United Kingdom
| | - Lance Turtle
- NIHR
Health Protection Research Unit in Emerging and Zoonotic Infections,
Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, United Kingdom
| | - Antonia Ho
- MRC-University
of Glasgow Centre for Virus Research, University
of Glasgow, Glasgow G61 1QH, United Kingdom
| | - Malcolm G. Semple
- NIHR
Health Protection Research Unit in Emerging and Zoonotic Infections,
Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool L69 7BE, United Kingdom
- Respiratory
Medicine, Alder Hey Children’s Hospital, Liverpool L12 2AP, United Kingdom
| | - Peter J. M. Openshaw
- Faculty
of Medicine, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom
| | - J. Kenneth Baillie
- Roslin
Institute, University of Edinburgh, Edinburgh EH25 9RG, United Kingdom
| | - Zoltán Takáts
- Section
of Bioanalytical Chemistry, Division of Systems Medicine, Department
of Metabolism, Digestion and Reproduction, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
- National
Phenome Centre, Imperial College London, Hammersmith Campus, IRDB Building, London W12 0NN, United Kingdom
| | - Matthew R. Lewis
- Section
of Bioanalytical Chemistry, Division of Systems Medicine, Department
of Metabolism, Digestion and Reproduction, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
- National
Phenome Centre, Imperial College London, Hammersmith Campus, IRDB Building, London W12 0NN, United Kingdom
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11
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Kim YE, Lee M, Lee YH, Kang ES, Cha BS, Lee BW. Proteinuria as a significant predictive factor for the progression of carotid artery atherosclerosis in non-albuminuric type 2 diabetes. Diabetes Res Clin Pract 2021; 181:109082. [PMID: 34627943 DOI: 10.1016/j.diabres.2021.109082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 09/27/2021] [Accepted: 10/05/2021] [Indexed: 11/23/2022]
Abstract
AIMS This study aimed to evaluate the clinical significance of urine protein to creatinine ratio (uPCR) in relation to the cardiovascular risk associated with carotid artery intima-media thickness (cIMT) progression in subjects with type 2 diabetes (T2D) and normoalbuminuria. METHODS In this retrospective longitudinal study on T2D, we recruited 927 participants with normoalbuminuria (urine albumin to creatinine ratio [uACR] < 30 mg/g) whose cIMT was measured at baseline and after at least 1 year, and whose initial uPCR and uACR data were available. RESULTS Higher initial uPCR was positively correlated with a greater increment in maximal cIMT (β = 0.074, p = 0.028), and this correlation was significant even after adjusting for multiple confounding factors (β = 0.074, p = 0.046). High baseline uPCR was an independent predictive factor for the increased risk of maximal cIMT progression in a simple logistic regression model (OR, 1.41; 95% CI, [1.08-1.86]; p = 0.013). Even after adjusting for several confounding variables, higher uPCR was significantly associated with a higher risk of cIMT progression (OR, 1.48; 95% CI, [1.08-2.03]; p = 0.014). CONCLUSIONS These results suggest that high uPCR may be a useful predictive marker for the progression of carotid artery atherosclerosis, even in subjects with T2D and without albuminuria.
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Affiliation(s)
- Young-Eun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Minyoung Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-Ho Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Seok Kang
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Bong-Soo Cha
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byung-Wan Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
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12
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Ricciardi CA, Gnudi L. Kidney disease in diabetes: From mechanisms to clinical presentation and treatment strategies. Metabolism 2021; 124:154890. [PMID: 34560098 DOI: 10.1016/j.metabol.2021.154890] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 09/08/2021] [Accepted: 09/16/2021] [Indexed: 12/24/2022]
Abstract
Metabolic and haemodynamic perturbations and their interaction drive the development of diabetic kidney disease (DKD) and its progression towards end stage renal disease (ESRD). Increased mitochondrial oxidative stress has been proposed as the central mechanism in the pathophysiology of DKD, but other mechanisms have been implicated. In parallel to increased oxidative stress, inflammation, cell apoptosis and tissue fibrosis drive the relentless progressive loss of kidney function affecting both the glomerular filtration barrier and the renal tubulointerstitium. Alteration of glomerular capillary autoregulation is at the basis of glomerular hypertension, an important pathogenetic mechanism for DKD. Clinical presentation of DKD can vary. Its classical presentation, often seen in patients with type 1 diabetes (T1DM), features hyperfiltration and albuminuria followed by progressive fall in renal function. Patients can often also present with atypical features characterised by progressive reduction in renal function without albuminuria, others in conjunction with non-diabetes related pathologies making the diagnosis, at times, challenging. Metabolic, lipid and blood pressure control with lifestyle interventions are crucial in reducing the progressive renal function decline seen in DKD. The prevention and management of DKD (and parallel cardiovascular disease) is a huge global challenge and therapies that target haemodynamic perturbations, such as inhibitors of the renin-angiotensin-aldosterone system (RAAS) and SGLT2 inhibitors, have been most successful.
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Affiliation(s)
| | - Luigi Gnudi
- School of Cardiovascular Medicine & Science, King's College London, London, UK.
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13
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Buades JM, Craver L, Del Pino MD, Prieto-Velasco M, Ruiz JC, Salgueira M, de Sequera P, Vega N. Management of Kidney Failure in Patients with Diabetes Mellitus: What Are the Best Options? J Clin Med 2021; 10:2943. [PMID: 34209083 PMCID: PMC8268456 DOI: 10.3390/jcm10132943] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 06/22/2021] [Accepted: 06/25/2021] [Indexed: 11/25/2022] Open
Abstract
Diabetic kidney disease (DKD) is the most frequent cause of kidney failure (KF). There are large variations in the incidence rates of kidney replacement therapy (KRT). Late referral to nephrology services has been associated with an increased risk of adverse outcomes. In many countries, when patients reach severely reduced glomerular filtration rate (GFR), they are managed by multidisciplinary teams led by nephrologists. In these clinics, efforts will continue to halt chronic kidney disease (CKD) progression and to prevent cardiovascular mortality and morbidity. In patients with diabetes and severely reduced GFR and KF, treating hyperglycemia is a challenge, since some drugs are contraindicated and most of them require dose adjustments. Even more, a decision-making process will help in deciding whether the patient would prefer comprehensive conservative care or KRT. On many occasions, this decision will be conditioned by diabetes mellitus itself. Effective education should cover the necessary information for the patient and family to answer these questions: 1. Should I go for KRT or not? 2. If the answer is KRT, dialysis and/or transplantation? 3. Dialysis at home or in center? 4. If dialysis at home, peritoneal dialysis or home hemodialysis? 5. If transplantation is desired, discuss the options of whether the donation would be from a living or deceased donor. This review addresses the determinant factors with an impact on DKD, aiming to shed light on the specific needs that arise in the management and recommendations on how to achieve a comprehensive approach to the diabetic patient with chronic kidney disease.
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Affiliation(s)
- Juan M. Buades
- Department of Nephrology, Hospital Universitario Son Llàtzer, Balearic Islands, 07198 Palma de Mallorca, Spain
- Health Research Institute of the Balearic Islands (IdISBa), 07120 Palma de Mallorca, Spain
| | - Lourdes Craver
- Department of Nephrology, Hospital Universitario Arnau de Vilanova, 25198 Lleida, Spain;
| | - Maria Dolores Del Pino
- Department of Nephrology, Complejo Hospitalario Torrecárdenas de Almería, 04009 Almería, Spain;
| | - Mario Prieto-Velasco
- Department of Nephrology, Complejo Asistencial Universitario de Leon, 24001 León, Spain;
| | - Juan C. Ruiz
- Department of Nephrology, Valdecilla Hospital, University of Cantabria, 39008 Santander, Spain;
- Valdecilla Biomedical Research Institute (IDIVAL), Cardenal Herrera Oria S/N, 39011 Santander, Spain
| | - Mercedes Salgueira
- Department of Nephrology, Hospital Universitario Virgen Macarena, 41009 Seville, Spain;
- Biomedical Engineering Group, Medicine Department, University of Seville, 41092 Seville, Spain
- Center for Biomedical Research Network in Bioengineering Biomaterials and Nanomedicina (CIBER-BBN), 28029 Madrid, Spain
| | - Patricia de Sequera
- Department of Nephrology, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain;
- Medicine Department, Universidad Complutense de Madrid, 28031 Madrid, Spain
| | - Nicanor Vega
- Department of Nephrology, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Spain;
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14
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Role of Microalbuminuria and Hypoalbuminemia as Outcome Predictors in Critically Ill Patients. Crit Care Res Pract 2021; 2021:6670642. [PMID: 33953981 PMCID: PMC8057906 DOI: 10.1155/2021/6670642] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/09/2021] [Accepted: 04/01/2021] [Indexed: 11/25/2022] Open
Abstract
Background Assessment of microalbuminuria and hypoalbuminemia can be used as a good tool for the prediction of the ICU outcome in critically ill patients. Purpose To evaluate and compare the prognostic significance of microalbuminuria (albumin creatinine ratio (ACR)) and serum albumin level done on admission and after twenty-four hours for the critically ill patients. Methodology. Sixty ICU patients were involved in a prospective cohort study (mean age was 44.4 ± 16.7 years, and 78.3% were males). Patients were divided into 2 groups according to mortality (survivors and nonsurvivors) and were subjected to laboratory measurement of the mentioned biomarkers on admission and after twenty-four hours. Results There were 34 patients (56.67%) in group A (survivors) and 26 patients (43.33%) in group B (nonsurvivors). Albumin creatinine ratio on admission (ACR1) and albumin creatinine ratio after 24 hours (ACR2) were significantly lower in survivors than nonsurvivors (P values were <0.001 for both). Serum albumin level after 24 hours of admission was significantly higher in survivors than nonsurvivors (P value 0.02) while admission serum albumin was not significantly different between both groups (P value was 0.1). There was a positive correlation between ACR2 and ICU stay and mechanical ventilatory support with a strong positive correlation with the use of vasopressor therapy (r: 0.35, 0.58, and 0.73, respectively). P values were 0.005, <0.0001, and <0.0001, respectively. There was a positive correlation between ACR2 with APACHE II and SOFA scores (r: 0.46 and 0.43, respectively); P values were 0.001 and <0.0001, respectively. There was a moderate negative correlation between serum albumin on admission and after 24 hours and the duration of mechanical ventilation (r: −0.4 and −0.39, respectively) (P values were 0.001 and 0.002, respectively). By Cox regression analysis, two parameters were found to be an independent predictor of mortality in ICU patients which were age and using vasopressor treatment (P values = 0.01 and <0.001), while the other parameters were not independent predictors of mortality (P values were more than 0.05). Conclusions Microalbuminuria on admission and after 24 hours of ICU admission could be a good predictor of mortality in critically ill patients. The serum albumin level after 24 hours of admission can predict poor outcomes in critically ill patients.
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15
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Pursnani N, Agrawal P, Gautam A, Jain A, S M, M K. Renoprotective effects of teneligliptin: An observational study. JOURNAL OF DIABETOLOGY 2021. [DOI: 10.4103/jod.jod_42_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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16
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Zanetti M, Barazzoni R, Kiwanuka E, Vettore M, Vedovato M, Tessari P. Accelerated whole-body protein catabolism in subjects with type 2 Diabetes Mellitus and albuminuria. PLoS One 2020; 15:e0243638. [PMID: 33332405 PMCID: PMC7746191 DOI: 10.1371/journal.pone.0243638] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 11/24/2020] [Indexed: 11/18/2022] Open
Abstract
Background Albuminuria develops in ~40% of subjects with Type 2 Diabetes Mellitus (T2DM), and is often associated with malnutrition, severe comorbidities and decreased life expectancy. The association between albuminuria and altered whole body protein turnover in T2DM is currently unknown. Objective To assess whole body protein degradation and synthesis in type 2 diabetes with and without albuminuria. Methods Fourteen T2DM male subjects, with either increased [AER+] or normal [AER-] urinary albumin excretion rate, and eleven age-matched male healthy controls, were infused with phenylalanine [Phe] and tyrosine [Tyr] tracers. Post-absorptive rates of appearance (Ra) of Phe (= protein degradation) and Tyr, Phe hydroxylation to Tyr (Hy) (catabolic pathway), and Phe disposal to protein synthesis [PS], were determined. Results Phe and Tyr Ra were not different among the groups. However, in T2DM [AER+], the fraction of Phe disposal to hydroxylation was ~50% and ~25% greater than that of both controls and T2DM [AER-] (p<0.006 and p = 0.17, respectively). Conversely, as compared to controls, the fractional Phe disposal to PS was ~10% lower in T2DM [AER+] (p<0.006), and not different from that in T2DM [AER-]. As a consequence, in T2DM [AER+], the ratio between the fractional Phe disposal to hydroxylation and that to PS was ~70% greater (p = 0.005) than that in healthy controls, whereas in the T2DM [AER-] this ratio was ~30% greater than in controls (p = 0.19). Conclusions On the basis of the kinetics of the essential amino acid phenylalanine, T2DM subjects with increased AER exhibit a catabolic pattern of whole body protein turnover.
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Affiliation(s)
- Michela Zanetti
- Metabolism Division, Department of Medicine, University of Padova, Padova, Italy.,DSM, University of Trieste, Trieste, Italy
| | - Rocco Barazzoni
- Metabolism Division, Department of Medicine, University of Padova, Padova, Italy.,DSM, University of Trieste, Trieste, Italy
| | - Edward Kiwanuka
- Metabolism Division, Department of Medicine, University of Padova, Padova, Italy
| | - Monica Vettore
- Metabolism Division, Department of Medicine, University of Padova, Padova, Italy
| | - Monica Vedovato
- Metabolism Division, Department of Medicine, University of Padova, Padova, Italy
| | - Paolo Tessari
- Metabolism Division, Department of Medicine, University of Padova, Padova, Italy
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17
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Brandt-Jacobsen NH, Johansen ML, Rasmussen J, Forman JL, Holm MR, Faber J, Rossignol P, Schou M, Kistorp C. Effect of high-dose mineralocorticoid receptor antagonist eplerenone on urinary albumin excretion in patients with type 2 diabetes and high cardiovascular risk: Data from the MIRAD trial. DIABETES & METABOLISM 2020; 47:101190. [PMID: 32919068 DOI: 10.1016/j.diabet.2020.08.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 08/21/2020] [Accepted: 08/23/2020] [Indexed: 12/20/2022]
Abstract
AIM As mineralocorticoid receptor antagonists (MRAs) may possess renoprotective effects in type 2 diabetes (T2D), it was decided to investigate the impact of high-dose MRA on prespecified secondary endpoints-namely, change in urinary albumin-creatinine ratio (UACR) and 24-h ambulatory blood pressure-in the MIRAD trial. METHODS This was a double-blind clinical trial in which T2D patients at high risk of or with established cardiovascular disease (CVD) were randomized to either high-dose (100-200 mg) eplerenone or a dose-matched placebo as an add-on to background antihypertensive treatment for 26 weeks. Safety was evaluated by the incidence of hyperkalaemia and kidney-related adverse events. RESULTS A total of 140 patients were enrolled (70 in each group). Baseline UACR was 17 mg/g (geometric mean; 95% CI: 13-22); this decreased by 34% in the eplerenone group compared with the placebo group at week 26 (95% CI: -51% to -12%; P = 0.005). There was no significant decrease in 24-h systolic blood pressure (SBP) due to treatment (-3 mmHg; 95% CI: -6 to 1; P = 0.150). However, the observed change in 24-h SBP correlated with the relative change in UACR in the eplerenone group (r = 0.568, P < 0.001). Mean baseline (± SD) estimated glomerular filtration rate (eGFR) was 85 (± 18.6) mL/min/1.73 m2, and 12 (± 9%) had an eGFR of 41-59 mL/min/1.73 m2. No significant differences in the incidence of mild hyperkalaemia (≥ 5.5 mmol/L; eplerenone vs placebo: 6 vs 2, respectively; P = 0.276) and no severe hyperkalaemia (≥ 6.0 mmol/L) were observed. CONCLUSION The addition of high-dose eplerenone to T2D patients at high risk of CVD can markedly reduce UACR with an acceptable safety profile.
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Affiliation(s)
- Niels H Brandt-Jacobsen
- Department of Endocrinology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Marie Louise Johansen
- Department of Endocrinology-Internal Medicine, Copenhagen University Hospital, Herlev-Gentofte Hospital
| | - Jon Rasmussen
- Department of Endocrinology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Department of Internal Medicine, Holbæk Hospital, Denmark
| | - Julie L Forman
- Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Section of Biostatistics, Department of Public Health, University of Copenhagen, Denmark
| | | | - Jens Faber
- Department of Endocrinology-Internal Medicine, Copenhagen University Hospital, Herlev-Gentofte Hospital; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Patrick Rossignol
- Université de Lorraine, INSERM CIC Plurithémathique 1433, UMRS 1116 INSERM, CHRU Nancy, and FCRIN INI-CRCT, Nancy, France
| | - Morten Schou
- Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; Department of Cardiology, Copenhagen University Hospital, Herlev-Gentofte Hospital, Denmark
| | - Caroline Kistorp
- Department of Endocrinology, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
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18
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Delitsikou V, Jarad G, Rajaram RD, Ino F, Rutkowski JM, Chen CD, Santos CXC, Scherer PE, Abraham CR, Shah AM, Feraille E, Miner JH, de Seigneux S. Klotho regulation by albuminuria is dependent on ATF3 and endoplasmic reticulum stress. FASEB J 2019; 34:2087-2104. [PMID: 31907991 DOI: 10.1096/fj.201900893r] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 10/31/2019] [Accepted: 11/13/2019] [Indexed: 12/11/2022]
Abstract
Proteinuria is associated with renal function decline and cardiovascular mortality. This association may be attributed in part to alterations of Klotho expression induced by albuminuria, yet the underlying mechanisms are unclear. The presence of albumin decreased Klotho expression in the POD-ATTAC mouse model of proteinuric kidney disease as well as in kidney epithelial cell lines. This downregulation was related to both decreased Klotho transcription and diminished protein half-life, whereas cleavage by ADAM proteases was not modified. The regulation was albumin specific since it was neither observed in the analbuminemic Col4α3-/- Alport mice nor induced by exposure of kidney epithelial cells to purified immunoglobulins. Albumin induced features of ER stress in renal tubular cells with ATF3/ATF4 activation. ATF3 and ATF4 induction downregulated Klotho through altered transcription mediated by their binding on the Klotho promoter. Inhibiting ER stress with 4-PBA decreased the effect of albumin on Klotho protein levels without altering mRNA levels, thus mainly abrogating the increased protein degradation. Taken together, albuminuria decreases Klotho expression through increased protein degradation and decreased transcription mediated by ER stress induction. This implies that modulating ER stress may improve proteinuria-induced alterations of Klotho expression, and hence renal and extrarenal complications associated with Klotho loss.
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Affiliation(s)
- Vasiliki Delitsikou
- Department of Cell Physiology and Metabolism, Faculty of Medicine, CMU, University of Geneva, Geneva, Switzerland.,Laboratory of Nephrology, Department of Internal Medicine Specialties, HUG, Geneva, Switzerland
| | - George Jarad
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Renuga Devi Rajaram
- Department of Cell Physiology and Metabolism, Faculty of Medicine, CMU, University of Geneva, Geneva, Switzerland.,Laboratory of Nephrology, Department of Internal Medicine Specialties, HUG, Geneva, Switzerland
| | - Frédérique Ino
- Department of Cell Physiology and Metabolism, Faculty of Medicine, CMU, University of Geneva, Geneva, Switzerland.,Laboratory of Nephrology, Department of Internal Medicine Specialties, HUG, Geneva, Switzerland
| | - Joseph M Rutkowski
- Touchstone Diabetes Centre, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas.,Department of Medical Physiology, Texas A&M College of Medicine, College Station, Texas
| | - Ci-Di Chen
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts
| | - Celio X C Santos
- King's College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine & Sciences, London, UK
| | - Philipp E Scherer
- Touchstone Diabetes Centre, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas
| | - Carmela R Abraham
- Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts
| | - Ajay M Shah
- King's College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine & Sciences, London, UK
| | - Eric Feraille
- Department of Cell Physiology and Metabolism, Faculty of Medicine, CMU, University of Geneva, Geneva, Switzerland
| | - Jeffrey H Miner
- Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Sophie de Seigneux
- Department of Cell Physiology and Metabolism, Faculty of Medicine, CMU, University of Geneva, Geneva, Switzerland.,Laboratory of Nephrology, Department of Internal Medicine Specialties, HUG, Geneva, Switzerland
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19
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Rahman A, Sherajee SJ, Rafiq K, Kobara H, Masaki T, Nakano D, Morikawa T, Konishi Y, Imanishi M, Nishiyama A. The angiotensin II receptor-neprilysin inhibitor LCZ696 attenuates the progression of proteinuria in type 2 diabetic rats. J Pharmacol Sci 2019; 142:124-126. [PMID: 31924408 DOI: 10.1016/j.jphs.2019.09.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 09/03/2019] [Accepted: 09/18/2019] [Indexed: 01/30/2023] Open
Abstract
We examined the effects of the angiotensin receptor-neprilysin inhibitor LCZ696 on overt proteinuria and renal injury in type 2 diabetic Otsuka-Long- Evans-Tokushima-Fatty (OLETF) rats. Aged OLETF rats were also treated with either valsartan or valsartan plus hydralazine for comparison. LCZ696 caused greater attenuation of the progression of proteinuria than either valsartan alone or valsartan combined with hydralazine. Reduced glomerular injury and tubulointerstitial fibrosis were also observed in LCZ696-treated rats. Moreover, LCZ696 prevented increases in blood urea nitrogen (BUN) and creatinine levels. These data suggest that LCZ696 elicits a reno-protective effect against type 2 diabetes with overt proteinuria.
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Affiliation(s)
- Asadur Rahman
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Shamshad J Sherajee
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Kazi Rafiq
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Daisuke Nakano
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Takashi Morikawa
- Division of Hypertension and Nephrology, Osaka General Hospital, Osaka, Japan
| | - Yoshio Konishi
- Division of Hypertension and Nephrology, Osaka General Hospital, Osaka, Japan
| | - Masahito Imanishi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
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Fayed A, Rahman Tohamy IA, Kahla H, Elsayed NM, El Ansary M, Saadi G. Urinary podocyte-associated mRNA profile in Egyptian patients with diabetic nephropathy. Diabetes Metab Syndr 2019; 13:2849-2854. [PMID: 31425946 DOI: 10.1016/j.dsx.2019.07.048] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 07/29/2019] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Podocyte injury and subsequent excretion in urine play a crucial role in the pathogenesis and progression of diabetic nephropathy (DN). Quantification of messenger RNA expression in urinary sediment by real-time PCR is emerging as a noninvasive method of screening DN-associated biomarkers. We aimed to study the expression of podocyte-associated genes in urinary sediment and their relation to disease severity in type 2 diabetic Egyptian patients with diabetic nephropathy. METHOD ology: Sixty patients with type 2 diabetes mellitus were recruited in addition to twenty non diabetic healthy volunteers. Relative mRNA abundance of nephrin, podocalyxin, and podocin were quantified, and correlations between target mRNAs and clinical parameters were examined. RESULTS The urinary mRNA levels of all genes studied were significantly higher in diabetics compared with controls (p < 0.001), and mRNA levels increased with DN progression. Urinary mRNA levels of all target genes positively correlated with both UAE and HbA1c. The expression of nephrin, podocalyxin, and podocin mRNA correlated with serum creatinine {(r = 0.397, p value = 0.002), (r = 0.431, p value = 0.001), (r = 0.433, p value = 0.001) respectively}. CONCLUSION The urinary mRNA profiles of nephrin, podocalyxin, and podocin were found to increase with the progression of DN, which suggested that quantification of podocyte-associated molecules will be useful biomarkers of DN.
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Affiliation(s)
- Ahmed Fayed
- Nephrology unit, Internal Medicine Department, School of Medicine, Cairo University, Egypt.
| | | | - Hala Kahla
- Endocrinology unit, Internal Medicine Department, School of Medicine, Cairo University, Egypt
| | - Naglaa M Elsayed
- Endocrinology unit, Internal Medicine Department, School of Medicine, Cairo University, Egypt
| | - Mervat El Ansary
- Clinical Pathology Department, School of Medicine, Cairo University, Egypt
| | - Gamal Saadi
- Nephrology unit, Internal Medicine Department, School of Medicine, Cairo University, Egypt
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Saadi G, El Meligi A, El-Ansary M, Alkemary A, Ahmed G. Evaluation of microRNA-192 in patients with diabetic nephropathy. THE EGYPTIAN JOURNAL OF INTERNAL MEDICINE 2019. [DOI: 10.4103/ejim.ejim_89_18] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Kopel J, Pena-Hernandez C, Nugent K. Evolving spectrum of diabetic nephropathy. World J Diabetes 2019; 10:269-279. [PMID: 31139314 PMCID: PMC6522757 DOI: 10.4239/wjd.v10.i5.269] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/13/2019] [Accepted: 05/13/2019] [Indexed: 02/05/2023] Open
Abstract
Diabetes remains an important health issue as more patients with chronic and uncontrolled diabetes develop diabetic nephropathy (DN), which classically presents with proteinuria followed by a progressive decrease in renal function. However, an increasing proportion of DN patients have a decline in kidney function and vascular complications without proteinuria, known as non-proteinuric DN (NP-DN). Despite the increased incidence of NP-DN, few clinical or experimental studies have thoroughly investigated the pathophysiological mechanisms and targeted treatment for this form of DN. In this review, we will examine the differences between conventional DN and NP-DN and consider potential pathophysiological mechanisms, diagnostic markers, and treatment for both DN and NP-DN. The investigation of the pathophysiology of NP-DN should provide additional insight into the cardiovascular factors influencing renal function and disease and provide novel treatments for the vascular complications seen in diabetic patients.
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Affiliation(s)
- Jonathan Kopel
- Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79416, United States
| | - Camilo Pena-Hernandez
- Department of Internal Medicine, Division of Nephrology, Lubbock, TX 79430, United States
| | - Kenneth Nugent
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, United States
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Sagoo MK, Gnudi L. Diabetic nephropathy: Is there a role for oxidative stress? Free Radic Biol Med 2018; 116:50-63. [PMID: 29305106 DOI: 10.1016/j.freeradbiomed.2017.12.040] [Citation(s) in RCA: 130] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 12/27/2017] [Accepted: 12/31/2017] [Indexed: 01/06/2023]
Abstract
Oxidative stress has been implicated in the pathophysiology of diabetic nephropathy. Studies in experimental animal models of diabetes strongly implicate oxidant species as a major determinant in the pathophysiology of diabetic kidney disease. The translation, in the clinical setting, of these concepts have been quite disappointing, and new theories have challenged the concepts that oxidative stress per se plays a role in the pathophysiology of diabetic kidney disease. The concept of mitochondrial hormesis has been introduced to explain this apparent disconnect. Hormesis is intended as any cellular process that exhibits a biphasic response to exposure to increasing amounts of a substance or condition: specifically, in diabetic kidney disease, oxidant species may represent, at determined concentration, an essential and potentially protective factor. It could be postulated that excessive production or inhibition of oxidant species formation might result in an adverse phenotype. This review discusses the evidence underlying these two apparent contradicting concepts, with the aim to propose and speculate on potential mechanisms underlying the role of oxidant species in the pathophysiology of diabetic nephropathy and possibly open future more efficient therapies to be tested in the clinical settings.
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Affiliation(s)
- Manpreet K Sagoo
- School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre of Research Excellence, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, UK
| | - Luigi Gnudi
- School of Cardiovascular Medicine & Sciences, British Heart Foundation Centre of Research Excellence, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, UK.
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Cherney DZI, Zinman B, Inzucchi SE, Koitka-Weber A, Mattheus M, von Eynatten M, Wanner C. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2017; 5:610-621. [PMID: 28666775 DOI: 10.1016/s2213-8587(17)30182-1] [Citation(s) in RCA: 262] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 05/08/2017] [Accepted: 05/09/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND In a pooled analysis of short-term trials, short-term treatment with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin reduced albuminuria in patients with type 2 diabetes and prevalent albuminuria. In this exploratory analysis of the EMPA-REG OUTCOME trial, we report the short-term and long-term effects of empagliflozin on albuminuria in patients with type 2 diabetes and established cardiovascular disease, according to patients' baseline albuminuria status. METHODS In this randomised, double-blind, placebo-controlled trial at 590 sites in 42 countries, we randomly assigned patients aged 18 years and older with type 2 diabetes and established cardiovascular disease (1:1:1) to empagliflozin 10 mg, empagliflozin 25 mg, or placebo in addition to standard of care until at least 691 patients experienced an adjudicated event included in the primary outcome. We did the randomisation with a computer-generated random-sequence and interactive voice-response and web-response system, stratified by HbA1c, BMI, region, and estimated glomerular filtration rate. Patients, investigators, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary efficacy and safety endpoints of this trial have been reported previously. Here, we report urinary albumin-to-creatinine ratio (UACR) data for the pooled empagliflozin group versus placebo according to albuminuria status at baseline (normoalbuminuria: UACR <30 mg/g; microalbuminuria: UACR ≥30 to ≤300 mg/g; and macroalbuminuria: UACR >300 mg/g). We did the analysis with mixed-model repeated measures including prespecified and post-hoc tests. This study is completed and registered with ClinicalTrials.gov, number NCT01131676. FINDINGS Between Sept 1, 2010, and April 22, 2013, we randomly assigned 7028 patients to treatment groups and 7020 patients received treatment. At baseline, we had UACR data for 6953 patients: 4171 (59% of treated patients; 1382 assigned to placebo and 2789 assigned to empagliflozin) had normoalbuminuria, 2013 (29%; 675 assigned to placebo and 1338 assigned to empagliflozin) had microalbuminuria, and 769 (11%; 260 assigned to placebo and 509 assigned to empagliflozin) had macroalbuminuria. Median treatment duration was 2·6 years (IQR 2·0-3·4; 136 weeks) and median observation time was 3·1 years (2·2-3·6; 164 weeks). After short-term treatment at week 12, the placebo-adjusted geometric mean ratio of UACR change from baseline with empagliflozin was -7% (95% CI -12 to -2; p=0·013) in patients with normoalbuminuria, -25% (-31 to -19; p<0·0001) in patients with microalbuminuria, and -32% (-41 to -23; p<0·0001) in patients with macroalbuminuria. The reductions in UACR were maintained with empagliflozin in all three groups compared with placebo during long-term treatment when measured at 164 weeks. At follow-up, after cessation of treatment for a median of 34 or 35 days, UACR was lower in the empagliflozin versus placebo group in those with baseline microalbuminuria (placebo-corrected adjusted geometric mean ratio of relative change from baseline with empagliflozin: -22%, 95% CI -32 to -11; p=0·0003) or macroalbuminuria (-29%, -44 to -10; p=0·0048), but not for patients with baseline normoalbuminuria (1%, -8 to 10; p=0·8911). Patients treated with empagliflozin were more likely to experience a sustained improvement from microalbuminuria to normoalbuminuria (hazard ratio [HR] 1·43, 95% CI 1·22 to 1·67; p<0·0001) or from macroalbuminuria to microalbuminuria or normoalbuminuria (HR 1·82, 1·40 to 2·37; p<0·0001), and less likely to experience a sustained deterioration from normoalbuminuria to microalbuminuria or macroalbuminuria (HR 0·84, 0·74 to 0·95; p=0·0077). The proportions of patients with any adverse events, serious adverse events, and adverse events leading to discontinuation increased with worsening UACR status at baseline, but were similar between treatment groups. The proportion of patients with genital infections was greater with empagliflozin than placebo in all subgroups by UACR status. INTERPRETATION These results support short-term and long-term benefits of empagliflozin on urinary albumin excretion, irrespective of patients' albuminuria status at baseline. FUNDING Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance.
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Affiliation(s)
- David Z I Cherney
- Department of Medicine and Department of Physiology, Division of Nephrology, University Health Network, University of Toronto, Toronto, ON, Canada; Toronto General Hospital, Toronto, ON, Canada.
| | - Bernard Zinman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Silvio E Inzucchi
- Section of Endocrinology, Yale School of Medicine, New Haven, CT, USA
| | | | | | | | - Christoph Wanner
- Division of Nephrology, Würzburg University Clinic, Würzburg, Germany
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Low Rice Intake Is Associated with Proteinuria in Participants of Korea National Health and Nutrition Examination Survey. PLoS One 2017; 12:e0170198. [PMID: 28081248 PMCID: PMC5231352 DOI: 10.1371/journal.pone.0170198] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Accepted: 01/02/2017] [Indexed: 11/19/2022] Open
Abstract
Little is known about the risk factors of proteinuria in the Asian population. On the basis of the association between rice intake patterns and chronic diseases, we hypothesized that rice intake patterns are associated with proteinuria in the Asian population. Data, including data regarding rice intake frequency and dipstick urinalysis results, from the Korea National Health and Nutrition Examination Survey in 1998, 2001, 2005, and 2007 were analyzed. The study involved 19,824 participants who were older than 20 years of age. Low rice intake was defined as consumption of rice ≤ 1 time/day. Proteinuria was defined as dipstick urinalysis protein ≥ 1 positive. Among the 19,824 participants, the prevalence of low rice intake and proteinuria were 17.3% and 2.9%, respectively. The low rice intake group showed a higher rate of proteinuria than the non-low rice intake group did (3.8% vs. 2.7%, P < 0.001). In multivariate logistic regression analysis, the odds ratio (OR) of low rice intake for proteinuria was 1.54 (95% confidence interval (CI): 1.25-1.89; P < 0.001). Low rice intake was also independently associated with high blood pressure (OR: 1.43, 95% CI: 1.31-1.56; P < 0.001) and diabetes (OR: 1.43, 95% CI: 1.27-1.62; P < 0.001). In conclusion, low rice intake was found to be independently associated with proteinuria in the Asian population, which might have been affected by the associations of low rice intake with high blood pressure and diabetes. Future prospective studies are needed to confirm the results of this study.
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Chen CH, Wu HY, Wang CL, Yang FJ, Wu PC, Hung SC, Kan WC, Yang CW, Chiang CK, Huang JW, Hung KY. Proteinuria as a Therapeutic Target in Advanced Chronic Kidney Disease: a Retrospective Multicenter Cohort Study. Sci Rep 2016; 6:26539. [PMID: 27198863 PMCID: PMC4873744 DOI: 10.1038/srep26539] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 05/04/2016] [Indexed: 01/10/2023] Open
Abstract
Current evidence of proteinuria reduction as a surrogate target in advanced chronic kidney disease (CKD) is incomplete due to lack of patient-pooled database. We retrospectively studied a multicenter cohort of 1891 patients who were enrolled in the nationwide multidisciplinary pre-end stage renal disease care program with a baseline glomerular filtration rate (GFR) <45 mL/min/1.73 m(2) and followed longitudinally to investigate the effect of the change in proteinuria on renal death (defined as composite of dialysis and death occurring before initiation of dialysis). The group with a change in proteinuria ≤0.30 g/g (n = 1261) had lower cumulative probabilities of renal death (p < 0.001). In a linear regression model, a higher baseline proteinuria and a greater increase in proteinuria were associated with faster annual GFR decline. Cox's analysis showed that every 1 unit increase in natural log(baseline proteinuria, 10 g/g) and every 0.1 g/g increase in the change in proteinuria resulted in 67% (HR = 1.67, 95% CI: 1.46-1.91) and 1% (HR = 1.01, 95% CI: 1.01-1.01) greater risk of renal death respectively after adjusting for the effects of the other covariates. Our study provided a patient-based evidence to support proteinuria as a therapeutic target in advanced CKD.
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Affiliation(s)
- Chang-Hsu Chen
- Division of Nephrology, Tungs’ Taichung MetroHarbor Hospital, Taichung City, Taiwan
| | - Hon-Yen Wu
- Division of Nephrology, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Chieh-Li Wang
- Division of Nephrology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei City, Taiwan
| | - Feng-Jung Yang
- Division of Nephrology, National Taiwan University Hospital Yun-Lin Branch, Yunlin County, Taiwan
| | - Pei-Chen Wu
- Division of Nephrology, Da Chien General Hospital, Miaoli County, Taiwan
| | - Szu-Chun Hung
- Division of Nephrology, Buddhist Tzu Chi Hospital Taipei Branch, New Taipei City, Taiwan
| | - Wei-Chih Kan
- Department of Nephrology, Chi Mei Medical Center, Tainan City, Taiwan
| | - Chung-Wei Yang
- Division of Nephrology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu City, Taiwan
| | - Chih-Kang Chiang
- Division of Nephrology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei City, Taiwan
| | - Jenq-Wen Huang
- Division of Nephrology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei City, Taiwan
| | - Kuan-Yu Hung
- Division of Nephrology, Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei City, Taiwan
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Panduru NM, Saraheimo M, Forsblom C, Thorn LM, Gordin D, Wadén J, Tolonen N, Bierhaus A, Humpert PM, Groop PH. Urinary adiponectin is an independent predictor of progression to end-stage renal disease in patients with type 1 diabetes and diabetic nephropathy. Diabetes Care 2015; 38:883-90. [PMID: 25720601 DOI: 10.2337/dc14-2276] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2014] [Accepted: 02/05/2015] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We investigated the predictive value of urinary adiponectin (uADP) for the progression of diabetic nephropathy (DN) as well as for the principal determinants of uADP concentrations. RESEARCH DESIGN AND METHODS uADP was measured in 2,090 patients with type 1 diabetes followed for a median of 5.8 (4.4-6.9) years and in 111 subjects without diabetes. Progression was defined as a change in albuminuria (albumin excretion rate [AER]) to a higher stage or development of end-stage renal disease (ESRD). Various Cox regression and competing risk models were used to evaluate the predictive value of uADP for DN progression. The added predictive benefit to AER or estimated glomerular filtration rate (eGFR) was estimated by the area under the receiver operating characteristic curve, integrated discrimination improvement (IDI), continuous net reclassification improvement (NRI), and other statistical indexes. The determinants of uADP were investigated by multiple regression analyses. RESULTS uADP was an independent predictor of progression to ESRD (hazard ratio 1.60, P < 0.001) and was an even better predictor than AER (P = 0.04) or as good as eGFR (P = 0.79). Furthermore, uADP added a significant benefit when used together with AER (NRI 0.794, P = 0.03; IDI 0.115, P < 0.0001) or eGFR (NRI 0.637, P < 0.001; IDI 0.087, P < 0.0001). The common determinants of uADP were glycemic control, tubular injury, and AER. CONCLUSIONS uADP is a strong independent predictor of DN progression from macroalbuminuria to ESRD and adds a significant predictive benefit to current biomarkers in patients with type 1 diabetes.
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Affiliation(s)
- Nicolae M Panduru
- 2nd Clinical Department, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Markku Saraheimo
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
| | - Carol Forsblom
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
| | - Lena M Thorn
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
| | - Daniel Gordin
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
| | - Johan Wadén
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
| | - Nina Tolonen
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
| | - Angelika Bierhaus
- Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany
| | | | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland Division of Nephrology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
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Jang CM, Hyun YY, Lee KB, Kim H. Insulin resistance is associated with the development of albuminuria in Korean subjects without diabetes. Endocrine 2015; 48:203-10. [PMID: 24676759 DOI: 10.1007/s12020-014-0242-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Accepted: 03/12/2014] [Indexed: 12/13/2022]
Abstract
Previous studies have shown that insulin resistance is associated with the development of albuminuria. However, most studies are done on a background of diabetes or metabolic syndrome and there is little data from general population. The aim of this study is to define the effect of insulin resistance on the development of albuminuria in healthy individuals without diabetes. We analyzed 60,047 participants without baseline diabetes or chronic kidney disease, who underwent at least two health maintenance visits at a 2-year interval between 2002 and 2009 at a tertiary hospital in Korea. We measured the incidence of albuminuria at the second examination and calculated the odds ratio for the development of albuminuria according to the quintile of the homeostasis model assessment of insulin resistance (HOMA-IR). After 2 years, 880 cases of incident albuminuria were observed. The cumulative incidences of albuminuria were 1.08, 1.50, 1.35, 1.47, and 1.92% for the 1st to 5th quintiles of HOMA-IR. On multivariate logistic analysis, the odds ratios for incident albuminuria compared to those in the 1st quintile were 1.38 (95% CI 1.10-1.73; P=0.006), 1.23 (95% CI 0.97-1.55; P=0.087), 1.32 (95% CI 1.04-1.67; P=0.020), and 1.66 (95% CI 1.31-2.09; P<0.001) in the 2nd, 3rd, 4th, and 5th quintiles, respectively. A high level of insulin resistance assessed with HOMA-IR was associated with the development of albuminuria in relatively healthy subjects without diabetes. Further research is needed to verify the role of insulin resistance in the development of albuminuria and renal injury.
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Affiliation(s)
- Cheol Min Jang
- Department of Internal Medicine, School of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, 29 Saemunan-ro, Jongro-Gu, Seoul, 110-746, Republic of Korea
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Dong X, Wu D, Jia C, Ruan Y, Feng X, Wang G, Liu J, Shen Y, Li H, Li L. Low ankle-brachial index is associated with early-stage chronic kidney disease in type 2 diabetic patients independent of albuminuria. PLoS One 2014; 9:e109641. [PMID: 25354133 PMCID: PMC4212907 DOI: 10.1371/journal.pone.0109641] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2014] [Accepted: 09/08/2014] [Indexed: 01/13/2023] Open
Abstract
AIMS The role of low ankle-brachial index (ABI) in early-stage chronic kidney disease (CKD) is not fully known. This study was designed to investigate the prevalence of low ABI in early-stage CKD defined as an estimated glomerular filtration rate (eGFR) between 60-89 ml/min/1.73 m2 of type 2 diabetic patients without albuminuria and to determine the association between the low ABI and mildly decreased eGFR. METHODS The cross-sectional study enrolled 448 type 2 diabetic patients with normoalbuminuria. The patients were stratified into two groups according to the CKD-EPI eGFR level: the normal group with eGFR level ≥ 90 mL/min/1.73 m2 and the lower group with eGFR of 60-89. ABI was categorized as normal (1.0-1.39), low-normal (0.9-0.99), and low (<0.9). Both stepwise forward multiple linear regression and binary logistic regression analyses were performed to examine the association between ABI categories and eGFR levels and to assess the relation of low ABI and early-stage CKD. RESULTS The prevalence of low ABI in early-stage CKD of type 2 diabetic patients without albuminuria was 39.5%. Low ABI was associated with an approximate 3-fold greater risk of early-stage CKD in bivariate logistic regression analysis, and remained significantly associated with a 2.2 fold risk (95% confidence interval: 1.188-4.077; P = 0.012) after adjusting traditional chronic kidney disease risk factors. CONCLUSIONS There was a high prevalence of low ABI in early-stage CKD patients of type 2 diabetes with normoalbuminuria and a close relation between low ABI and early-stage CKD, suggesting that we should pay much more attention to the patients who have only mildly decreased eGFR and normoalbuminuria but have already had a low ABI in clinic work and consider the preventive therapy in early stage.
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Affiliation(s)
- Xuehong Dong
- Departments of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
| | - Dingting Wu
- Departments of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
| | - Chengfang Jia
- Departments of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
| | - Yu Ruan
- Departments of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
| | - Xiaocheng Feng
- Departments of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
| | - Guoxing Wang
- Departments of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
| | - Jun Liu
- Departments of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
| | - Yi Shen
- Department of Epidemiology and Health Statistics School of Public Health, Zhejiang University, Hangzhou, P. R. China
| | - Hong Li
- Departments of Endocrinology and Metabolism, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, P. R. China
| | - Lianxi Li
- Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, P. R. China
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'Progressive diabetic nephropathy. How useful is microalbuminuria?: contra'. Kidney Int 2014; 86:50-7. [PMID: 24717301 DOI: 10.1038/ki.2014.98] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2013] [Revised: 12/29/2013] [Accepted: 01/24/2014] [Indexed: 12/24/2022]
Abstract
The concept of microalbuminuria has been central to the development of clinical practice and research in the area of diabetic kidney disease (DKD). However, in recent times, the value of a paradigm of DKD based solely on microalbuminuria has been questioned. Although both the absolute level and rate of change of microalbuminuria are linked to the development and progression of DKD, microalbuminuria on its own lacks the necessary sensitivity or specificity to accurately predict kidney outcomes for people with diabetes. The development of microalbumiuria can no longer be viewed as a committed and irreversible stage of DKD, as spontaneous remission is now reported as a common occurrence. In addition, the absence of microalbuminuria or its progression to proteinuria does not signify that an individual patient is safe from a progressive decline in glomerular filtration rate (GFR). Furthermore, although reductions in albuminuria within the microalbuminuric range can be linked to a slower GFR decline in observational studies, this relationship has not been robustly demonstrated in intervention studies. Conclusions regarding the kidney health of individuals with diabetes will continue to be flawed if an inappropriate emphasis is placed on the presence or absence of albuminuria or changes in albuminuria within the microalbuminuric range. This has important implications in terms of undermining the value of microalbuminuria as a surrogate renal end point for intervention trials. There is a need to develop broader models of progressive DKD that include novel pathways and risk markers apart from those related to the traditional 'albuminuric pathway' to renal impairment.
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Morita M, Hanai K, Uchigata Y. Urinary type IV collagen as a predictor for the incidence of microalbuminuria in young patients with Type 1 diabetes. Diabet Med 2014; 31:213-8. [PMID: 24103009 DOI: 10.1111/dme.12317] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/04/2013] [Indexed: 02/03/2023]
Abstract
AIMS To clarify whether urinary type IV collagen-to-creatinine ratio is a predictor for the incidence of microalbuminuria in patients with Type 1 diabetes. METHODS A longitudinal observational cohort study was conducted; the subjects included normoalbuminuric patients diagnosed with Type 1 diabetes before the age of 30 years and who were less than 40 years old at the start of the observation. In total, 225 patients were enrolled (age, mean ± SD: 25 ± 5 years; male: 32.9%). The endpoint was the incidence of microalbuminuria, defined as 30 mg/g Cr ≤ urinary albumin-to-creatinine ratio < 300 mg/g Cr. Patients were divided into two groups based on the median of urinary type IV collagen-to-creatinine ratio levels. RESULTS During the median follow-up period of 8.8 years (range 1.0-12.8 years), 13 patients with high urinary type IV collagen-to-creatinine ratio progressed to microalbuminuria. Meanwhile, only one patient with low urinary type IV collagen-to-creatinine ratio reached the endpoint. Kaplan-Meier estimates for the time to reach the endpoint were significantly faster for patients with a high ratio than for those with a low ratio (log-rank test, P < 0.001). In the multivariate Cox hazard analysis, the hazard ratio for patients with high vs. low urinary type IV collagen-to-creatinine ratio was 13.51 (95% CI 1.59-115.02, P = 0.017). When urinary type IV collagen-to-creatinine ratio was treated as a continuous variable, logarithmically transformed urinary type IV collagen-to-creatinine ratio, but not baseline albumin-to-creatinine ratio, was independently associated with reaching the endpoint (hazard ratio 19.23, 95% CI 1.53-242.30, P = 0.022). CONCLUSIONS Urinary type IV collagen may be an important predictor for the incidence of microalbuminuria in young patients with Type 1 diabetes.
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Affiliation(s)
- M Morita
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo; Department of Internal Medicine 1, Shimane University Faculty of Medicine, Shimane, Japan
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Viberti G, Karalliedde J. Commentary: the birth of microalbuminuria: a milestone in the history of medicine. Int J Epidemiol 2014; 43:18-20. [PMID: 24374830 DOI: 10.1093/ije/dyt256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Affiliation(s)
- Giancarlo Viberti
- Unit for Metabolic Medicine, Cardiovascular Division, King's College London School of Medicine, London, UK
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Geng DF, Sun WF, Yang L, En G, Wang JF. Antiproteinuric effect of angiotensin receptor blockers in normotensive patients with proteinuria: a meta-analysis of randomized controlled trials. J Renin Angiotensin Aldosterone Syst 2013; 15:44-51. [PMID: 23378528 DOI: 10.1177/1470320312474054] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
INTRODUCTION The objective of this article is to evaluate the antiproteinuric effect of angiotensin receptor blockers (ARBs) in normotensive patients with proteinuria. MATERIALS AND METHODS We reviewed randomized controlled trials assessing ARBs treatment in patients with normotension and proteinuria. Data concerning the study design, patient characteristics, and outcomes were extracted. Ratio of means was calculated by using the generalized inverse variance method. RESULTS Eight trials involving 866 patients were included in this study. Compared with a control group, ARBs group was associated with a significant reduction in urinary protein excretion (ratio of means 0.53, 95% CI 0.44-0.64). Subgroup analysis shows that ARBs therapy resulted in a significant decrease in urinary protein excretion in diabetic patients with microalbuminuria or nondiabetic nephropathy with overt proteinuria (ratio of means 0.57, 95% CI 0.47-0.69 and 0.46, 95% CI 0.26-0.83, respectively), in a Western population or an Asian population (ratio of means 0.61, 95% CI 0.54-0.69 and 0.49, 95% CI 0.37-0.64, respectively), and in patients followed up for one to three months or three to 12 months (ratio of means 0.62, 95% CI 0.54-0.70 and 0.49, 95% CI 0.38-0.63, respectively). CONCLUSIONS The data suggest that ARBs may have beneficial effects in preventing the progression of proteinuria in normotensive patients with renal disease.
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Cardiorenal syndrome: pathophysiology and potential targets for clinical management. Nat Rev Nephrol 2012; 9:99-111. [PMID: 23247571 DOI: 10.1038/nrneph.2012.279] [Citation(s) in RCA: 123] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Combined dysfunction of the heart and the kidneys, which can be associated with haemodynamic impairment, is classically referred to as cardiorenal syndrome (CRS). Cardiac pump failure with resulting volume retention by the kidneys, once thought to be the major pathophysiologic mechanism of CRS, is now considered to be only a part of a much more complicated phenomenon. Multiple body systems may contribute to the development of this pathologic constellation in an interconnected network of events. These events include heart failure (systolic or diastolic), atherosclerosis and endothelial cell dysfunction, uraemia and kidney failure, neurohormonal dysregulation, anaemia and iron disorders, mineral metabolic derangements including fibroblast growth factor 23, phosphorus and vitamin D disorders, and inflammatory pathways that may lead to malnutrition-inflammation-cachexia complex and protein-energy wasting. Hence, a pathophysiologically and clinically relevant classification of CRS based on the above components would be prudent. With the existing medical knowledge, it is almost impossible to identify where the process has started in any given patient. Rather, the events involved are closely interrelated, so that once the process starts at a particular point, other pathways of the network are potentially activated. Current therapies for CRS as well as ongoing studies are mostly focused on haemodynamic adjustments. The timely targeting of different components of this complex network, which may eventually lead to haemodynamic and vascular compromise and cause refractoriness to conventional treatments, seems necessary. Future studies should focus on interventions targeting these components.
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Dei Cas A, Gnudi L. VEGF and angiopoietins in diabetic glomerulopathy: how far for a new treatment? Metabolism 2012; 61:1666-73. [PMID: 22554833 DOI: 10.1016/j.metabol.2012.04.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Revised: 04/02/2012] [Accepted: 04/02/2012] [Indexed: 01/15/2023]
Abstract
Diabetic nephropathy (DN) is the major cause of end-stage renal disease in Western countries and its prevalence continues to increase (United States Renal Data System 2010, http://www.usrds.org/). Treatments currently utilised for DN provide only partial renoprotection, hence the need to identify new targets for therapeutic intervention. Metabolic and haemodynamic abnormalities have been implicated in the pathogenesis of DN, triggering the activation of intracellular signaling molecules that lead to the dysregulation of vascular growth factors and cytokines, such as vascular endothelial growth factor (VEGF) and angiopoietins, important players in the functional and structural regulation of the glomerular filtration barrier. This review focuses on the importance of VEGF-A and angiopoietins in kidney physiology and in the diabetic kidney, exploring their potential therapeutic role in the prevention and delay of diabetic glomerulopathy.
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Affiliation(s)
- Alessandra Dei Cas
- Department of Internal Medicine and Biomedical Sciences, University of Parma, Italy.
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Propyl gallate plays a nephroprotective role in early stage of diabetic nephropathy associated with suppression of glomerular endothelial cell proliferation and angiogenesis. EXPERIMENTAL DIABETES RESEARCH 2012; 2012:209567. [PMID: 22988451 PMCID: PMC3439983 DOI: 10.1155/2012/209567] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Revised: 07/09/2012] [Accepted: 07/10/2012] [Indexed: 01/15/2023]
Abstract
There is growing evidence suggesting that glomerular endothelial cell proliferation and angiogenesis may be responsible for the pathophysiological events in the early stage of diabetic nephropathy. This study was designed to investigate the factors related to glomerular endothelial cell proliferation and glomerular angiogenesis and assess the effect of propyl gallate on preventing these disorders in diabetic rats. We found that glomerular hypertrophy, glomerular mesangial matrix expansion, and albuminuria were significantly increased in DN rats. CD31+ endothelial cells significantly increased in glomerulus of diabetic rats. Double immunofluorescence staining showed some structurally defective vasculus tubes in glomerulus. Real-time PCR and western blot demonstrated the glomerular eNOS expression remained at the same level, while remarkable decreased NO productions and suppressed eNOS activities were observed in diabetic rats. Treatment with propyl gallate improved glomerular pathological changes, reduced endothelial cell proliferation, decreased albuminuria, and restored eNOS activity, but did not alter eNOS expression. These data suggest that endothelial cell proliferation and immature angiogenesis may be the contributors to progression of DN. Propyl gallate is a potential novel therapeutic agent on prevention of diabetic nephropathy.
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Komorowsky CV, Brosius FC, Pennathur S, Kretzler M. Perspectives on systems biology applications in diabetic kidney disease. J Cardiovasc Transl Res 2012; 5:491-508. [PMID: 22733404 PMCID: PMC3422674 DOI: 10.1007/s12265-012-9382-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2012] [Accepted: 05/22/2012] [Indexed: 12/18/2022]
Abstract
Diabetic kidney disease (DKD) is a microvascular complication of type 1 and 2 diabetes with a devastating impact on individuals with the disease, their families, and society as a whole. DKD is the single most frequent cause of incident chronic kidney disease cases and accounts for over 40% of the population with end-stage renal disease. Contributing factors for the high prevalence are the increase in obesity and subsequent diabetes combined with an improved long-term survival with diabetes. Environment and genetic variations contribute to DKD susceptibility and progressive loss of kidney function. How the molecular mechanisms of genetic and environmental exposures interact during DKD initiation and progression is the focus of ongoing research efforts. The development of standardized, unbiased high-throughput profiling technologies of human DKD samples opens new avenues in capturing the multiple layers of DKD pathobiology. These techniques routinely interrogate analytes on a genome-wide scale generating comprehensive DKD-associated fingerprints. Linking the molecular fingerprints to deep clinical phenotypes may ultimately elucidate the intricate molecular interplay in a disease stage and subtype-specific manner. This insight will form the basis for accurate prognosis and facilitate targeted therapeutic interventions. In this review, we present ongoing efforts from large-scale data integration translating "-omics" research efforts into improved and individualized health care in DKD.
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Affiliation(s)
- Claudiu V. Komorowsky
- Department of Internal Medicine, Division of Nephrology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Frank C. Brosius
- Department of Internal Medicine, Division of Nephrology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Subramaniam Pennathur
- Department of Internal Medicine, Division of Nephrology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Matthias Kretzler
- Department of Internal Medicine, Division of Nephrology, University of Michigan Medical School, Ann Arbor, MI, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA
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Conway BR, Manoharan D, Manoharan D, Jenks S, Dear JW, McLachlan S, Strachan MWJ, Price JF. Measuring urinary tubular biomarkers in type 2 diabetes does not add prognostic value beyond established risk factors. Kidney Int 2012; 82:812-8. [PMID: 22718188 DOI: 10.1038/ki.2012.218] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Tubulointerstitial disease plays an important role in the pathophysiology of diabetic kidney disease. To determine whether biomarkers of tubular injury could predict renal outcome and mortality in patients with type 2 diabetes, we measured urinary levels of kidney injury molecule-1 (KIM-1) and glycoprotein non-metastatic melanoma B (Gpnmb), both normalized to the urinary creatinine, in 978 individuals from the Edinburgh Type 2 Diabetes Study. At baseline, 238 patients had an estimated glomerular filtration rate (eGFR) below 60 ml/min/1.73 m2 while 147 and 15 patients had microalbuminuria or overt proteinuria, respectively. Both the urine KIM-1 and Gpnmb to creatinine ratios correlated with the urinary albumin to creatinine ratio, the duration of diabetes, and the stringency of glycemic control but not with blood pressure or baseline eGFR. Higher ratios of each marker were associated with a faster decline in kidney function during 4 years of follow-up; however, this was not independent of the urinary albumin to creatinine ratio. Higher KIM-1, but not Gpnmb ratios were associated with an increased risk of mortality, but this association was no longer significant after adjustment for other risk factors, in particular albuminuria. Thus, tubular injury in persons with type 2 diabetes may contribute to the decline in kidney function; however, measuring the urinary concentration of these two tubular biomarkers does not confer additional prognostic information beyond established risk factors.
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Affiliation(s)
- Bryan R Conway
- University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science, Queen's Medical Research Institute, Metabolic Unit, Western General Hospital, Edinburgh, UK.
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Proinflammatory effects of C-Peptide in different tissues. Int J Inflam 2012; 2012:932725. [PMID: 22762010 PMCID: PMC3384941 DOI: 10.1155/2012/932725] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2012] [Revised: 03/23/2012] [Accepted: 04/27/2012] [Indexed: 12/12/2022] Open
Abstract
Atherosclerosis is well known as an inflammatory disease that can lead to clinical complications such as heart attack or stroke. C-peptide as a cleavage product of proinsulin is in the last few decades known as an active peptide with a number of different effects on microvascular and macrovascular complications in type 2 diabetic patients. Patients with insulin resistance and early type 2 diabetes show elevated levels of C-peptide in blood. Several last findings demonstrated deposition of C-peptide in the vessel wall in ApoE-deficient mice and induction of local inflammation. Besides that, C-peptide has proliferative effects on human mesangial cells. This review discusses recently published proinflammatory effects of C-peptide in different tissues.
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Jim B, Ghanta M, Qipo A, Fan Y, Chuang PY, Cohen HW, Abadi M, Thomas DB, He JC. Dysregulated nephrin in diabetic nephropathy of type 2 diabetes: a cross sectional study. PLoS One 2012; 7:e36041. [PMID: 22615747 PMCID: PMC3355157 DOI: 10.1371/journal.pone.0036041] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 03/28/2012] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Podocyte specific proteins are dysregulated in diabetic nephropathy, though the extent of their expression loss is not identical and may be subject to different regulatory factors. Quantifying the degree of loss may help identify the most useful protein to use as an early biomarker of diabetic nephropathy. METHODOLOGY/PRINCIPAL FINDINGS Protein expression of synaptopodin, podocin and nephrin were quantified in 15 Type 2 diabetic renal biopsies and 12 control patients. We found statistically significant downregulation of synaptopodin (P<0.0001), podocin (P = 0.0002), and nephrin (P<0.0001) in kidney biopsies of diabetic nephropathy as compared with controls. Urinary nephrin levels (nephrinuria) were then measured in 66 patients with Type 2 diabetes and 10 healthy controls by an enzyme-linked immunosorbent assay (Exocell, Philadelphia, PA). When divided into groups according to normo-, micro-, and macroalbuminuria, nephrinuria was found to be present in 100% of diabetic patients with micro- and macroalbuminuria, as well as 54% of patients with normoalbuminuria. Nephrinuria also correlated significantly with albuminuria (rho = 0.89, p<0.001), systolic blood pressure (rho = 0.32, p = 0.007), and correlated negatively with serum albumin (rho = -0.48, p<0.0001) and eGFR (rho = -0.33, p = 0.005). CONCLUSIONS/SIGNIFICANCE These data suggest that key podocyte-specific protein expressions are significantly and differentially downregulated in diabetic nephropathy. The finding that nephrinuria is observed in a majority of these normoalbuminuric patients demonstrates that it may precede microalbuminuria. If further research confirms nephrinuria to be a biomarker of pre-clinical diabetic nephropathy, it would shed light on podocyte metabolism in disease, and raise the possibility of new and earlier therapeutic targets.
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Affiliation(s)
- Belinda Jim
- Division of Nephrology, Department of Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York, United States of America.
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Gnudi L. Cellular and molecular mechanisms of diabetic glomerulopathy. Nephrol Dial Transplant 2012; 27:2642-9. [DOI: 10.1093/ndt/gfs121] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
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Zhang M, Liu M, Xiong M, Gong J, Tan X. Schisandra chinensis fruit extract attenuates albuminuria and protects podocyte integrity in a mouse model of streptozotocin-induced diabetic nephropathy. JOURNAL OF ETHNOPHARMACOLOGY 2012; 141:111-118. [PMID: 22353431 DOI: 10.1016/j.jep.2012.02.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 02/03/2012] [Accepted: 02/06/2012] [Indexed: 05/31/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Schisandra chinensis fruit is widely used in Chinese medicine for the treatment of hepatic, renal, heart, cerebrovascular and infectious diseases. AIM OF THE STUDY To investigate the effects of Schisandra chinensis fruit extract (SE) on albuminuria and podocyte injury as well as the underlying mechanism in the mouse model of streptozotocin (STZ)-induced diabetic nephropathy and in cultured mouse podocyte cells. MATERIALS AND METHODS SE was orally administrated in STZ-induced diabetic nephropathy mice for 7 weeks, at a daily dose of 5g/kg body weight. The urinary albumin/creatinine ratio and urine albumin excretion rate were measured at the 6th and 9th week of the experiment. The extent of glomerulosclerosis and extracellular matrix deposition were determined by periodic acid-silver methenamine and Masson's trichrome staining. The amount of podocytes and the integrity of the slit diaphragm were detected by immunohistological staining of podocyte markers, Wilms' tumor 1 and nephrin. Alpha-smooth muscle actin, E-cadherin and plasminogen activator inhibitor-1 were measured by western blot and immunohistological staining to evaluate the level of epithelial-to-mesenchymal transition (EMT). Real-time reverse transcription PCR was used to detect the mRNA level of E-cadherin, alpha-SMA and snail in cultured podocyte cells. RESULTS Treatment with SE significantly decreased the urine albumin excretion rate and urinary albumin/creatinine ratio. In addition, SE attenuated glomerulosclerosis and protected against podocyte loss and integrity of the slit diaphragm. Furthermore, SE effectively prevented the EMT of podocytes caused by diabetic nephropathy. CONCLUSIONS Our studies suggest that SE might be beneficial for diabetic nephropathy. The effects of SE on attenuating albuminuria and glomerulosclerosis are possibly mediated by preserving podocyte integrity through suppressing EMT.
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MESH Headings
- Administration, Oral
- Albuminuria/etiology
- Albuminuria/genetics
- Albuminuria/metabolism
- Albuminuria/pathology
- Albuminuria/prevention & control
- Animals
- Biomarkers/metabolism
- Blotting, Western
- Cells, Cultured
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/drug therapy
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/drug therapy
- Diabetes Mellitus, Type 1/metabolism
- Diabetic Nephropathies/etiology
- Diabetic Nephropathies/genetics
- Diabetic Nephropathies/metabolism
- Diabetic Nephropathies/pathology
- Diabetic Nephropathies/prevention & control
- Epithelial-Mesenchymal Transition/drug effects
- Fruit
- Gene Expression Regulation/drug effects
- Immunohistochemistry
- Male
- Mice
- Mice, Inbred C57BL
- Phytotherapy
- Plant Extracts/administration & dosage
- Plant Extracts/isolation & purification
- Plant Extracts/pharmacology
- Plants, Medicinal
- Podocytes/drug effects
- Podocytes/metabolism
- Podocytes/pathology
- Protective Agents/administration & dosage
- Protective Agents/isolation & purification
- Protective Agents/pharmacology
- RNA, Messenger/metabolism
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Schisandra/chemistry
- Time Factors
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Affiliation(s)
- Mianzhi Zhang
- Nephrology Division, Gongan Hospital, 78 Nanjin Road, Tianjin 300040, China
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Vasic D, Spyrantis A, Durst R, Bach H, Vogt S, Rottbauer W, Walcher D. C-peptide induces human renal mesangial cell proliferation in vitro, activating Src-kinase, PI-3 kinase and ERK1/2. Mol Cell Endocrinol 2012; 351:337-41. [PMID: 22269094 DOI: 10.1016/j.mce.2012.01.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2011] [Revised: 01/09/2012] [Accepted: 01/09/2012] [Indexed: 11/29/2022]
Abstract
BACKGROUND Elevated levels of C-peptide have been found in patients with insulin resistance and early type 2 diabetes. These patients are at greater risk to develop micro- and macrovascular complications. Since diabetic nephropathy involves glomerular hyperproliferation, the present study evaluates the role of C-peptide on human renal mesangial cell proliferation. METHODS AND RESULTS C-peptide induces proliferation of human renal mesangial cells in a concentration-dependent manner with a maximal 2.6±0.4-fold induction at 10 nmol/L (P<0.05 compared with unstimulated cells; n=6), as revealed by [3H]-thymidine incorporation experiments. The proliferative effect of C-peptide is prevented by Src-kinase inhibitor-PP2, PI-3 kinase inhibitor-LY294002, and the ERK1/2 inhibitor-U126. Moreover, C-peptide induces phosphorylation of Src, as well as activation of PI-3 kinase and ERK1/2. Furthermore, C-peptide induces cyclin D1 expression as well as phosphorylation of retinoblastoma protein (Rb). CONCLUSIONS These results demonstrate an active role of C-peptide on the proliferation of human renal mesangial cells in vitro involving PI-3 kinase and MAP kinase signaling pathways, suggesting a possible role of C-peptide in glomerular hyperproliferation in patients with diabetic nephropathy.
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Affiliation(s)
- Dusica Vasic
- Department of Internal Medicine II, University of Ulm, Germany
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Albuminurie. Internist (Berl) 2012; 53:38-44. [DOI: 10.1007/s00108-011-2891-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Asano S, Suzuki A, Ishii J, Sekiguchi-Ueda S, Shibata M, Yoshino Y, Nakamura K, Akiyama Y, Kitagawa F, Sakuishi T, Fujita T, Itoh M. Use of a new high-sensitivity assay for cardiac troponin T to stratify the risk of cardiovascular disease in outpatients with type-2 diabetes. Diabetol Int 2011. [DOI: 10.1007/s13340-011-0057-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
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Martinez HG, Quinones MP, Jimenez F, Estrada CA, Clark K, Muscogiuri G, Sorice G, Musi N, Reddick RL, Ahuja SS. Critical role of chemokine (C-C motif) receptor 2 (CCR2) in the KKAy + Apoe -/- mouse model of the metabolic syndrome. Diabetologia 2011; 54:2660-8. [PMID: 21779871 PMCID: PMC4430553 DOI: 10.1007/s00125-011-2248-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2011] [Accepted: 06/03/2011] [Indexed: 11/25/2022]
Abstract
AIMS/HYPOTHESIS Chemokines and their receptors such as chemokine (C-C motif) receptor 2 (CCR2) may contribute to the pathogenesis of the metabolic syndrome via their effects on inflammatory monocytes. Increased accumulation of CCR2-driven inflammatory monocytes in epididymal fat pads is thought to favour the development of insulin resistance. Ultimately, the resulting hyperglycaemia and dyslipidaemia contribute to development of the metabolic syndrome complications such as cardiovascular disease and diabetic nephropathy. Our goal was to elucidate the role of CCR2 and inflammatory monocytes in a mouse model that resembles the human metabolic syndrome. METHODS We generated a model of the metabolic syndrome by backcrossing KKAy ( + ) with Apoe ( -/- ) mice (KKAy ( + ) Apoe ( -/- )) and studied the role of CCR2 in this model system. RESULTS KKAy ( + ) Apoe ( -/- ) mice were characterised by the presence of obesity, insulin resistance, dyslipidaemia and increased systemic inflammation. This model also manifested two complications of the metabolic syndrome: atherosclerosis and diabetic nephropathy. Inactivation of Ccr2 in KKAy (+) Apoe ( -/- ) mice protected against the metabolic syndrome, as well as atherosclerosis and diabetic nephropathy. This protective phenotype was associated with a reduced number of inflammatory monocytes in the liver and muscle, but not in the epididymal fat pads; circulating levels of adipokines such as leptin, resistin and adiponectin were also not reduced. Interestingly, the proportion of inflammatory monocytes in the liver, pancreas and muscle, but not in the epididymal fat pads, correlated significantly with peripheral glucose levels. CONCLUSIONS/INTERPRETATION CCR2-driven inflammatory monocyte accumulation in the liver and muscle may be a critical pathogenic factor in the development of the metabolic syndrome.
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Affiliation(s)
- H G Martinez
- South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, TX, USA
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47
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Hellemons ME, Persson F, Bakker SJL, Rossing P, Parving HH, De Zeeuw D, Lambers Heerspink HJ. initial angiotensin receptor blockade-induced decrease in albuminuria is associated with long-term renal outcome in type 2 diabetic patients with microalbuminuria: a post hoc analysis of the IRMA-2 trial. Diabetes Care 2011; 34:2078-83. [PMID: 21788629 PMCID: PMC3161288 DOI: 10.2337/dc11-0324] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE We aimed to investigate the individual impact of initial responses in urinary albumin excretion (UAE) and systolic blood pressure (SBP) to angiotensin II receptor blocker (ARB) treatment on long-term renal outcome in patients with type 2 diabetes and microalbuminuria. RESEARCH DESIGN AND METHODS In a post hoc analysis of the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA)-2 trial we first assessed the individual variability in UAE and SBP response (0-6 months) in 531 subjects. Subsequently, we analyzed the individual effect of both response parameters on renal outcome defined as change in estimated glomerular filtration rate (eGFR) during 2 years of follow-up. RESULTS The median reductions in UAE and SBP in the population were -18% and -11 mmHg, respectively. In irbesartan-treated patients, 85 (24.4%) had a robust (>median) reduction in UAE but not in SBP (discordant SBP response) and 67 (19.3%) had a robust (>median) reduction in SBP but not in UAE (discordant UAE response). The degree of reduction in UAE was independently associated with the rate of eGFR decline (P = 0.0037). SBP showed a similar trend (P = 0.087). The relation between a larger UAE reduction and a slower rate of renal function decline was present in both cohorts with a SBP change above and below the median. CONCLUSIONS Within an individual, UAE response to ARB therapy may be discordant from SBP response. The initial change in UAE was independently associated with eGFR slope; the more UAE reduction the less eGFR decline, irrespective of the SBP change. These results suggest that in microalbuminuric patients with type 2 diabetes, UAE should be monitored after initiation of therapy and a separate target for renoprotective therapy.
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Affiliation(s)
- Merel E Hellemons
- Department of Clinical Pharmacology, University ofGroningen, Groningen, the Netherlands.
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48
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Abstract
Lowering blood pressure may confer a benefit to diabetic microvascular complications comparable with glycemic control. Hypertension is causally related to kidney outcomes and is a risk factor for the development of diabetic retinopathy. The prevalence of hypertension increases as kidney disease progresses, so that it coexists with diabetes in up to 80% of those with overt nephropathy. A significant number of patients have hypertension or rising blood pressures in earlier stages, or even before microvascular complications appear. Because microalbuminuria markedly increases the risk of overt nephropathy as well as of cardiovascular complications, primary prevention (i.e., preventing or delaying the onset of microalbuminuria) continues to be explored, predominantly through use of renin-angiotensin blockade. Available data reviewed suggest that primary prevention through blood pressure reduction is more likely to benefit select groups (those with hypertension, cardiovascular risks, or old age). This review discusses the relationship between hypertension, diabetes, and kidney disease, the rationale for primary prevention, and the data that led to that conclusion.
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Affiliation(s)
- Mark E Williams
- Renal Unit, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USA.
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Nelson RG. Is treatment of nephropathy in type 1 diabetes efficacious but ineffective? J Am Soc Nephrol 2011; 22:402-4. [PMID: 21355059 DOI: 10.1681/asn.2011010076] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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